Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods

Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Primary research Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods Zhenyu Xie, Xin Li, YuZhen He, Song Wu, Shiyue Wang, Jianjian Sun, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-35109/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Nov, 2020 Read the published version in BMC Cancer → Version 1 posted You are reading this latest preprint version Abstract Background: Interleukin-1 receptor antagonist (IL1RN) has been reported as a biomarker of many cancers. However, the biological function of IL1RN in papillary thyroid carcinoma (PTC) remains undetermined. Methods: We obtained IL1RN expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and IL1RN methylation analysis were performed via LinkedOmics. The correlations between IL1RN and immune infiltrates were investigated via ESTIMATE, TIMER and TISIDB. We analyzed the association of IL1RN expression with pancancer overall survival (OS) via Gene Expression Profiling Interactive Analysis (GEPIA). Results: IL1RN showed higher expression levels and lower methylation levels in PTC tissues than in normal tissues. Higher IL1RN expression was significantly associated with shorter progression-free survival (PFS), advanced tumor stage, tumor metastasis, increased incidence of BRAF mutations, and decreased incidence of N-RAS and H-RAS mutations. Genes coexpressed with IL1RN participate primarily in immune-related pathways. IL1RN expression was positively correlated with immune infiltration, tumor progression and poor overall survival for all cancers. Conclusions: IL1RN is a good prognostic and diagnostic biomarker for PTC. IL1RN may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of IL1RN expression and biological function. Additionally, IL1RN was shown to have broad prognostic value in a pancancer cohort. Cancer Biology IL1RN papillary thyroid carcinoma diagnostic biomarker prognostic biomarker cancer immunity IL-1 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1 Introduction Thyroid carcinoma (THCA) is the most common endocrine malignancy worldwide [ 1 ]. The incidence of THCA has increased sharply over the past 3 decades [ 2 ]. Papillary thyroid carcinoma (PTC) is the major subtype of THCA, accounting for more than 90% of cases [ 3 ]. The clinical course of PTC is generally indolent, and the cancer-specific mortality of PTC is low compared to that of other cancers [ 4 ]. However, the incidence of cervical lymph node metastasis is high, which leads to local recurrence and poor prognosis [ 5 ]. The main task for the future is to identify high-risk patients and to give them appropriate treatment and care [ 6 ]. Therefore, further studies are required to explore the underlying mechanisms of tumorigenesis as well as identify additional biomarkers that predict prognosis and serve as therapeutic targets. The interleukin-1 (IL-1) family of cytokines are the most effective molecules in the innate immune system [ 7 ]. IL-1 receptor antagonist (IL1RN) was initially found as a natural antagonist of IL-1[ 8 ]. IL1RN is structurally related to IL-lα and IL-lβ but binds to IL-1 receptors on various target cells without inducing any discernible biological responses [ 9 ]. The balance between IL1RN and IL-1 plays a crucial role in many diseases, including cancer [ 10 ]. IL1RN has been studied in several cancers, including prostate carcinoma [ 11 – 12 ], cervical carcinoma [ 13 ], gastric carcinoma [ 14 ], bronchogenic carcinoma [ 15 ], endometrial cancer [ 16 ], lung cancer [ 17 ], ovarian cancer [ 18 ], oral malignancies [ 19 ], leukemia [ 20 ], and other cancers. Two structural variants of IL1RN have been described: the soluble extracellular form (sIL-1ra) and the intracellular form (icIL-1ra) [ 4 ]. Niedzwiecki, S. and colleagues assayed the serum levels of IL1RN in thyroid cancer patients. They measured preoperative IL1RN serum levels of patients with thyroid cancer, and the results showed that the serum concentrations of sIL-1ra were significantly higher in anaplastic carcinoma (ATC) and follicular carcinoma (FTC) patients [ 21 ]. To the best of our knowledge, no reports have been published to date concerning IL1RN expression in thyroid tissue. The objective of this study was to investigate the expression of IL1RN in normal and papillary thyroid cancer tissues by performing bioinformatics analysis to elucidate its possible role in tumor progression. 2 Materials And Methods 2.1 Expression level analysis The cohort that comprised 512 PTC and 58 normal thyroid samples was obtained from The Cancer Genome Atlas (TCGA) ( https://tcga-data.nci.nih.gov/tcga/ ). The clinical data, normalized RNA expression data, DNA methylation data and simple nucleotide variation data were downloaded from the TCGA data portal. The gene expression profiles of four independent datasets (GSE3467, GSE33630, GSE58545, and GSE60542) were downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database ( http://www.ncbi.nlm.nih.gov/geo/ ). The immunohistochemical staining images of IL1RN in PTC and normal tissues were obtained from The Human Protein Atlas ( https://www.proteinatlas.org ). 2.2 Diagnostic and prognostic value analysis ROC curves were plotted, and the area under the ROC curve was calculated using the ROCR package in R. The patients were divided into a high IL1RN expression group (H-IL1RN) and a low IL1RN expression group (L-IL1RN) according to the best matched value for the survival analysis. Kaplan-Meier survival curves were generated by the R survival package. The primary end point of the study was progression-free survival (PFS). Univariate and multivariate analyses were performed using the Cox regression model to assess the significance of various variables to survival. A chi-square test was performed to compare the clinical characteristics between the H-IL1RN group and the L-IL1RN group. 2.3 Gene functional enrichment analysis We identified the genes that were significantly positively or negatively correlated with IL1RN using the LinkedOmics website ( http://www.linkes.org/ ). The top 50 positively correlated genes and the top 50 negatively correlated genes were selected to build the heatmaps. These genes were inputted into the GO and KEGG websites to obtain the enriched GO terms and significant KEGG pathways. GO function annotation analysis was performed based on the GO database ( http://geneontology.org/page/go-database ), and KEGG pathway annotation analysis was performed based on the KEGG database ( http://www.kegg.jp/kegg/ko.html ). The protein-protein interaction (PPI) network with a confidence > 0.7 was constructed using STRING ( https://string-db.org ) and CytoScape version 3.7.2. 2.4 Tumor immunology analysis ESTIMATE used the single-sample gene-set enrichment analysis (ssGSEA) score to quantify the enrichment levels of immune gene signatures in tumors. The stromal, immune and ESTIMATE scores of TCGA PTC samples were computed using ESTIMATE, and then the tumor purity of each sample was inferred. The Tumor Immune Estimation Resource (TIMER) web server ( https://cistrome.shinyapps.io/timer/ ), a comprehensive analytic web tool, was used to analyze the correlation of IL1RN with infiltration of immune cells, including B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils and dendritic cells (DCs). We used TISIDB ( http://cis.hku.hk/TISIDB/ ), a web portal for investigation of tumor and immune system interaction, to determine the Spearman correlation between IL1RN expression and 28 TIL types, chemokines, immune-activating cytokines, immunosuppressive cytokines, major histocompatibility complex (MHC) molecules, and chemokine receptors. 2.5 Methylation-related analysis DNA methylation data were downloaded from the data portal of TCGA ( https://portal.gdc.cancer.gov/ ), and the DNA methylation levels of the PTC and control groups were then compared. Spearman correlation analysis was conducted to examine the associations between the methylation density and gene expression and between the methylation density and tumor purity. Additionally, we analyzed the correlation between IL1RN expression and the methylation level of each CpG site using the Spearman correlation test. The analysis of the relationship between methylation and the clinical characteristics and the GO and KEGG analyses were performed using linkedOmics. 2.6 Pancancer analysis The pancancer expression and survival analysis of IL1RN was performed using the online software Gene Expression Profiling Interactive Analysis (GEPIA) ( http://gepia.cancer-pku.cn/ ). We used TISIDB to analyze the relationships between IL1RN expression and overall survival (OS) in pancancer. Kaplan-Meier (K-M) curves were generated for pancancer using the TCGA cohort data. 2.7 Related mutant gene analysis The analysis of the relationship between IL1RN expression and PTC mutations was performed by linkedOmics. The IL1RN expression level was further compared between the groups with wild-type and mutant versions of BRAF, NRAS and HRAS. 2.8 Statistical analysis The t -test and Mann-Whitney U test were used for comparisons between two groups. The chi-square test was used to assess the differences in clinical parameters between the L-IL1RN and H-IL1RN groups. The Pearson and Spearman methods were used for correlation analysis. The log-rank method was used to calculate the significant p -values related to survival. R software (v3.6.0) and SPSS version 25.0 software were used for statistical processing. Visualization of data was performed with GraphPad Prism V.8.0 and R software. p < 0.05 was considered significant. 3 Results 3.1 The differential expression and diagnostic value of IL1RN The expression levels of IL1RN were initially analyzed in the TCGA cohort consisting of 512 PTC samples and 58 normal samples (Figure 1A). Furthermore, expression data from four independent PTC cohorts obtained from the Gene Expression Omnibus (GEO) (GSE3467, GSE33630, GSE58545, and GSE60542) were employed for validation (Figure 5A-D). Both the GEO and TCGA patient cohorts had significantly higher IL1RN mRNA expression in PTC tissues than in normal tissues (P<0.05). Elevated levels of IL1RN protein expression were observed in PTC tissues compared with those in normal tissues by immunohistochemistry performed using the IL1RN antibody CAB9633. (Figure 1C) ROC curves were constructed to evaluate the diagnostic value of IL1RN for PTC. The area under the ROC curve of the TCGA cohort was 0.7084 (Figure 1B) and that of each GEO cohort was 0.9753, 0.7279, 0.8868, and 0.8384, respectively. (Figure 5E-H) These results suggest the good positive diagnostic value of IL1RN for PTC. 3.2 Prognostic value and clinical significance of IL1RN The PTC samples from the TCGA cohort were divided into two groups according to the IL1RN expression level: the high-expression group (H-IL1RN) (n = 116) and the low-expression group (L-IL1RN) (n = 385). Differences in progression-free survival (PFS) between the two groups were analyzed by Kaplan-Meier analysis. (Figure 1D) The results showed that patients with high IL1RN expression had significantly shorter PFS than those with low expression (P=0.0034). However, the data for the multivariate analysis by the Cox regression model suggested that IL1RN expression was not a significant independent prognostic risk indicator for PTC (hazard ratio, 1.033; 95% confidence interval, 0.999−1.068, p > 0.05) (Table 1). Age was an independent predictor of poor prognosis (P＜0.05). To examine the clinical significance of IL1RN in PTC, the relationship between the expression level of IL1RN and clinical characteristics was investigated by the chi-square test (Table 2). The results suggested that IL1RN expression was significantly associated with age, clinical stage, N stage, T stage, pathologic type, BRAF mutations and RAS mutations. 3.3 Gene coexpression and pathway enrichment analysis We identified the genes that are significantly positively or negatively related to IL1RN. The result is presented as a volcano plot (Figure 2A). Red and green colors indicate a positive and negative correlation, respectively. The top 50 positively (Figure 2B) or negatively (Figure 2C) correlated genes are depicted by heatmaps. In addition, 2 hub genes (CCL20 and FN1) were identified from the protein–protein interaction (PPI) network (Figure 2D). GO enrichment analysis revealed that the identified genes were mainly enriched for the GO biological process terms “neutrophil mediated immunity”, “positive regulation of cytokine production”, “adaptive immune response” and “immune response-regulating signalling pathway” (Figure 2E). Further KEGG enrichment analysis suggested that the identified genes were mainly involved in pathways associated with “cell adhesion molecules (CAMs)”, “cytokine-cytokine receptor interaction”, and “phagosome” (Figure 2F). 3.4 Immune-related analysis of IL1RN Using ESTIMATE, the association between IL1RN expression and immune infiltrates was analyzed. We found that the H-IL1RN group showed a higher immune score (Figure 3B) and ESTIMATE score (Figure 3C) and lower tumor purity (Figure 3D) than the L-IL1RN group. No significant difference in the stromal score was found between the two groups (Figure 3A). The correlations between the IL1RN expression level and the infiltration of six immune cell types in PTC were estimated. The results demonstrated that the expression of IL1RN was found to be significantly correlated with the infiltration of immune cells, especially neutrophils and dendritic cells (Figure 3E). Correlations between IL1RN expression and 28 TIL types (Figure 3F), chemokines (Figure 3G), immune-activating cytokines (Figure S2A), immunosuppressive cytokines (Figure S2B), MHC molecules (Figure S2C), and chemokine receptors (S2D) in pancancer are shown in heatmaps. The correlation analysis results showed a good correlation between IL1RN expression and immune-related molecules. 3.5 Methylation-related analysis The data showed that the degree of IL1RN DNA methylation was higher in carcinoma tissues than in normal tissues (P<0.0001) (Figure 4A). To further determine the role of methylation, we performed a correlation analysis between the DNA methylation levels of IL1RN and the expression levels of IL1RN. As expected, DNA methylation was negatively correlated with IL1RN expression (R=-0.600, P=2.29e-50) (Figure 4B). Tumor purity was significantly positively associated with IL1RN methylation (R=0.447, P=7.49e-32) (Figure 4C). Patients with an advanced clinical stage (Figure 4D), advanced T stage (Figure 4E) and lymph node metastasis (Figure 4F) tended to have decreased IL1RN methylation levels. In the pathological subtype of PTC, the tall cell type variant of PTC had the lowest degree of methylation, followed by the classical type, and the follicular variant of PTC had the highest degree of methylation (Figure 4G). To further explore the associated functional changes in IL1RN methylation, GO (Figure 4I) and KEGG (Figure 4F) enrichment analyses were performed. The results showed that methylated IL1RN had the opposite effect of IL1RN. Furthermore, the most significant methylation sites are shown in Table 3. 3.6 Pancancer analysis of IL1RN We analyzed the IL1RN expression levels in different kinds of tumors via the GEPIA platform (Figure 6A). The results showed that the expression levels of IL1RN varied greatly in different cancer types. Of the 33 cancer types tested, 12 cancer types were associated with significantly increased IL1RN expression. Subsequently, the relationship between IL1RN and OS in pancancer was investigated (Figure 6B). Kaplan-Meier survival curves for the high IL1RN expression group (4745 patients) and low IL1RN expression group (4750 patients) indicated that increased IL1RN expression was associated with a shorter survival time in pancancer (HR=1.6, P<0.0001) (Figure 6C). The results showed that increased IL1RN expression levels were significantly associated with shorter OS in kidney renal clear cell carcinoma (KIRC) (Figure 6D), brain lower grade glioma (LGG) (Figure 6E), pancreatic adenocarcinoma (PADD) (Figure 6F) and uterine corpus endometrial carcinoma (UCEC) (Figure 6G). 3.7 Related mutant gene analysis The analysis of the relationship between IL1RN expression and PTC mutations was performed by linkedOmics (Figure S1A). The IL1RN expression level was further compared between the groups with wild-type and mutant variants of BRAF, NRAS and HRAS (Figure S1B-D). The expression of IL1RN was significantly higher in PTC with the BRAF mutant than in PTC with the wild type (Figure S1B). However, mutated NRAS (Figure S1C) and mutated HRAS (Figure S1D) were correlated with decreased IL1RN expression. 4 Discussion In this study, we first revealed high IL1RN expression in PTC tissues and its diagnostic and prognostic value by integrated bioinformatics analysis. To further explore the potential function of IL1RN, we identified genes related to IL1RN expression, and functional enrichment analyses were conducted. The results of the KEGG pathway and GO analyses revealed the significant enrichment of genes in immune-related pathways. Our work further demonstrated that high IL1RN expression was significantly associated with decreased tumor purity and increased immune infiltration. Through methylation-related analysis, we determined that DNA methylation might be a regulatory mechanism of IL1RN. In addition, the analysis of the relationship between IL1RN expression and PTC mutations showed that high IL1RN expression was associated with mutated BRAF, wild-type NRAS and wild-type HRAS. Finally, IL1RN shows superior prognostic value for various cancers according to the pancancer analysis. Niedzwiecki et al [ 21 ] revealed that the serum levels of IL1RN were upregulated in patients with ATC and PTC, but no statistically significant difference was found in PTC. We found that the expression of IL1RN was increased in PTC tissues compared with that in normal tissues in 1 TCGA cohort and 4 GEO cohorts and suggested that IL1RN might be used as a potential diagnostic biomarker in PTC. Our results were consistent with those of previous reports on the upregulation of IL1RN in cervical carcinoma [ 13 ], gastric cancer [ 14 ], lung cancer [ 15 ], and endometrial cancer tissues [ 16 ]. These findings are also basically consistent with the results of our pancancer study. In contrast to these findings, IL1RN exhibited low expression in oral squamous cell carcinomas (OSCCs) [ 19 ]. The results of this study showed the value of IL1RN as a clinical biomarker in PTC and emphasized its potential as a prognostic biomarker in PTC patients. PTC patients with high IL1RN expression had decreased PFS compared to those with low IL1RN expression. Furthermore, high expression of IL1RN was significantly correlated with clinical stage, lymph node metastasis and pathological type. Various studies have highlighted the significant association between IL1RN expression and poor cancer prognosis; however, the results of these studies are conflicting. Van Le et al. [ 16 ] revealed that there was a significant correlation between the stage of endometrioid carcinoma and the expression of IL1RN. In a study of colorectal cancer, serum IL1RN levels were correlated with tumor size, local and distant metastasis and vascular infiltration [ 32 ]. An increase in IL1RN expression was correlated significantly with lymph node and liver metastases in gastric carcinoma [ 14 ]. In contrast, low levels of IL1RN have been associated with increased disease severity in myeloma [ 22 ], colorectal cancer [ 23 ] and prostate cancer [ 24 ]. The underlying mechanism of IL1RN in cancer development and progression is complicated and unclear. In this study, functional enrichment analysis of genes coexpressed with IL1RN showed that IL1RN participates in immune-related biological processes. Consistent with our findings, previous studies have focused on the role of IL1RN in tumor immunity. A study of gastric carcinoma [ 14 ] pointed out that on the one hand, IL1RN may promote tumor growth via the impairment of cellular immunity; on the other hand, IL1RN enables malignant cells to escape host immune responses. Smith, D. R. et al. [ 15 ] revealed that increased IL1RN in bronchogenic carcinoma is not accompanied by increased IL-1β activity. The altered balance of IL1RN and IL-1β may result in impaired immune surveillance and cytotoxic activity. An experimental study of human glioblastoma cells showed that IL1RN secreted by tumor cells can counteract IL-1 function, which represents a potential escape mechanism that supports cancer growth [ 31 ]. In our study, IL1RN was significantly positively correlated with lymph node metastasis and tumor stage, so we speculated that IL1RN might also promote tumor aggressiveness and poor prognosis through immune-related mechanisms in PTC. IL1RN is an endogenous natural antagonist of IL-1[ 8 ], so the discovery of the interaction between IL1RN and IL-1 family molecules is a breakthrough in exploring the function of IL1RN. ONOZAKI et al. [ 25 ] reported that IL-1 is a cytocidal factor against several tumor cell lines. IL-1 may enhance cytotoxic T cell activity [ 29 ], the tumoricidal capacities of natural killer (NK) cells [ 30 ], and monocyte-mediated cytotoxicity [ 37 ]. Because IL-1 is critical for tumor immunity, elevation of IL1RN expression may result in a general environment favourable to tumor cells and enhance the metastatic and recurrence potential of tumors by changing local IL-1-dependent pathways. IL-1β has been reported as an anticancer factor that acts to suppress proliferation and reduce the invasive potential of human PTC cells [ 26 ]. sIL-1ra has been shown to block IL-1 function by binding to IL-1 receptors at the cell membrane level [ 27 ]. IcIL-1ra is postulated to inhibit intracellular IL-1 activity [ 28 ]. Therefore, whether IL1RN can block the function of IL-1 and inhibit the anticancer effect of IL-1β in PTC is worth further study. In our study, IL1RN showed a significant positive correlation with immune cells, which may be because a variety of immune cells can produce IL1RN through the stimulation of cytokines. Neutrophils produce IL1RN in response to granulocyte/macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) [ 34 ]. IL-4 and IL-10 have been reported to increase the production of IL1RN by human monocytes [ 35 ]. Yanagawa, H.et, al. reported that IL-13 increases IL1RN production by human alveolar macrophages [ 36 ]. It was reported that the apoptotic cell death of monocytes was enhanced by administration of recombinant IL1RN [ 33 ]. Our study also showed a significant correlation between IL1RN expression and various cytokines, which implied that IL1RN may play a complex role in tumor immunity. Our study suggests that methylation is a pretranscriptional regulatory mechanism for IL1RN. The methylation level of IL1RN was negatively correlated with its expression level and was also correlated with the disease stage, lymph node metastasis, and pathological type. IL1RN is likely to be a potential biomarker associated with the diagnosis and prognosis of PTC. However, although the diagnostic value, prognostic value and molecular functions of IL1RN in PTC have been analyzed through bioinformatics methods, the conclusions have not yet been confirmed by experiments. Therefore, further research is necessary to explore the role of IL1RN in PTC and the pharmacological value of IL1RN as a therapeutic target. 5 Conclusions IL1RN is a good prognostic and diagnostic biomarker of PTC. IL1RN may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of IL1RN expression and biological function. Additionally, IL1RN showed broad prognostic value in an analysis of a pancancer cohort. Declarations 1 Ethics approval and consent to participate Not applicable 2 Consent for publication Not applicable 3 Availability of data and materials The datasets analysed during the current study are available in The Cancer Genome Atlas (TCGA) (https://tcga-data.nci.nih.gov/tcga/) or the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). 4 Competing interests The authors declare that they have no competing interests. 5 Funding This research was supported by National Natural Science Foundation of China (81600602). 6 Authors’ contributions ZX designed the analytical strategies, performed data analyses and wrote the manuscript. XL performed data analysis and wrote the manuscript. YZH, SW, SYW, JS, YCH, YL and SJX performed data analysis. JZ conceived the research and wrote the manuscript. 7 Acknowledgements We would like to acknowledge the public databases including TCGA and GEO for their contributions to human medicine. Abbreviations IL1RN interleukin-1 receptor antagonist PTC papillary thyroid carcinoma TCGA The Cancer Genome Atlas OS overall survival GEPIA Gene Expression Profiling Interactive Analysis PFS progression-free survival THCA thyroid carcinoma IL-1 interleukin-1 sIL-1ra the soluble extracellular form of IL1RN icIL-1ra the intracellular form of IL1RN ATC anaplastic carcinoma FTC follicular carcinoma NCBI the National Center for Biotechnology Information GEO Gene Expression Omnibus H-IL1RN high IL1RN expression group L-IL1RN low IL1RN expression group PPI protein-protein interaction ssGSEA single-sample gene-set enrichment analysis TIMER Tumor Immune Estimation Resource DCs dendritic cells MHC major histocompatibility complex K-M Kaplan ‐ Meier CAMs cell adhesion molecules KIRC kidney renal clear cell carcinoma LGG lower grade glioma PADD pancreatic adenocarcinoma UCEC uterine corpus endometrial carcinoma OSCCs oral squamous cell carcinomas NK natural killer GM-CSF granulocyte/macrophage colony stimulating factor TNF-α tumor necrosis factor-α References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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Tables Table 1 Variables Univariate analysis Multivariate analysis Hazard ratio (95%CI) P value Hazard ratio (95%CI) P value Age(y ≥55/<55) 3.958(2.274−6.891) <0.001 2.582(1.312−5.083) 0.006 Gender(male/female) 1.471(0.834−2.592) 0.182 1.098(0.604−1.997) 0.758 Clinical stage 1.736(1.380−2.185) <0.001 1.301(0.968−1.748) 0.081 Radiation therapy 1.305(0.728−2.343) 0.372 1.205(0.651−2.233) 0.553 IL1RN 1.058(1.024−1.093) <0.001 1.033(0.999−1.068) 0.059 Table 2 Clinical parameters L-IL1RN(n=385,%) H-IL1RN(n=116,%) P-value Age(y) <55 261(67.8) 73(62.9) 0.330 ≥55 124(32.2) 43(37.1) Gender Female 282(73.2) 84(72.4) 0.859 Male 103(26.8) 32(27.6) Clinical stage I 224(58.5) 57(49.1) 0.001 II 47(12.3) 5(4.3) III 77(20.1) 34(29.3) IV 35(9.1) 20(17.2) NA 2 0 Metastasis M0 208(97.2) 74(96.1) 0.635 M1 6(2.8) 3(3.9) NA 171 39 N classification N0 189(54.8) 40(37.7) 0.002 N1 156(45.2) 66(62.3) NA 40 10 T classification T1 120(31.2) 22(19.3) <0.001 T2 135(35.1) 29(25.4) T3 116(30.1) 54(47.4) T4 14(3.6) 9(7.9) NA 0 2 Pathologic type Classical 268(69.6) 87(75.0) <0.001 Follicular 94(24.4) 7(6.0) Tall Cell 17(4.4) 19(16.4) Other 6(1.6) 3(2.6) BRAF Wild 179(48.5) 16(14.3) <0.001 Mutation 190(51.5) 96(85.7) NA 16 4 RAS Wild 311(84.3) 110(98.2) <0.001 Mutation 58(15.7) 2(1.8) NA 16 4 Table 3 Methylation site Spearman r P value cg01467417 -0.597 7.76E-50 cg02543462 -0.406 2.53E-21 cg01991967 -0.19 1.81E-05 cg03989987 -0.164 2.28E-04 cg10938446 -0.116 0.009 cg03703171 -0.107 0.016 cg11783497 -0.1 0.016 cg17669033 0.027 0.548 cg23041410 -0.022 0.625 cg06658391 0.018 0.687 cg25928199 NA NA cg25265126 NA NA cg02377053 NA NA Supplementary Files FigureS1.tif FigureS2.tif Cite Share Download PDF Status: Published Journal Publication published 24 Nov, 2020 Read the published version in BMC Cancer → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-35109","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Primary research","associatedPublications":[],"authors":[{"id":667034,"identity":"da8d1d41-fcd3-4db9-bd4d-598adf3e9725","order_by":0,"name":"Zhenyu Xie","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenyu","middleName":"","lastName":"Xie","suffix":""},{"id":667035,"identity":"3c551695-b01f-4696-9cda-fe08170a22ff","order_by":1,"name":"Xin Li","email":"","orcid":"https://orcid.org/0000-0003-0315-7321","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Li","suffix":""},{"id":667036,"identity":"a839bfa4-0ee7-48da-8303-9cb2ae1de01d","order_by":2,"name":"YuZhen He","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"YuZhen","middleName":"","lastName":"He","suffix":""},{"id":667037,"identity":"6b7582d0-91e3-4419-a095-c61f9bb30518","order_by":3,"name":"Song Wu","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Song","middleName":"","lastName":"Wu","suffix":""},{"id":667038,"identity":"94bf436c-a58a-4db3-bc20-7c42ed2fbe0f","order_by":4,"name":"Shiyue Wang","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shiyue","middleName":"","lastName":"Wang","suffix":""},{"id":667039,"identity":"18dc418d-b8b8-42bb-9385-9b6d80a41c12","order_by":5,"name":"Jianjian Sun","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jianjian","middleName":"","lastName":"Sun","suffix":""},{"id":667040,"identity":"69cd6b60-b919-457d-aba7-f7287d1dc1c3","order_by":6,"name":"Yuchen He","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuchen","middleName":"","lastName":"He","suffix":""},{"id":667041,"identity":"56ce1970-0e63-4c0b-9345-8ed4cd9442da","order_by":7,"name":"Yu Lun","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Lun","suffix":""},{"id":667042,"identity":"f7272001-3bdb-46d0-a0f4-9d41aeec5924","order_by":8,"name":"Shijie Xin","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shijie","middleName":"","lastName":"Xin","suffix":""},{"id":667043,"identity":"139525c9-7ea4-4cbd-97f5-acf73997c950","order_by":9,"name":"Jian Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYBACxmYQ0QAk2BsgAg3Ea+E5QKQWhDKJBCK1MLczP3v4c4ddnnzk46ebeRhsZDccYH72AL/D2MwNJM8kFxveTjO7zcOQZrzhAFAEvxYGMwnDNubEjbNz2IBaDiduOMDDJoFfC/s3icS2+sSNM8+AtPwnRguPmcTBtsOJ8yV4QFoOEKWlTLKx7XjiBp40s5tzDJKNZx5mM8OrxbD/+DbJn23VifPbDz+78abCTrbvePMz/FoaoAyDA2ASiJnxqQcCeTijAY+qUTAKRsEoGNkAABOSST6buUhEAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4448-0774","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Jian","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2020-06-12 04:39:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-35109/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-35109/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-020-07620-8","type":"published","date":"2020-11-25T02:37:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":1341216,"identity":"111696b6-cde6-4543-a4c4-281d9ecd594d","added_by":"auto","created_at":"2020-06-16 15:46:50","extension":"tif","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3322149,"visible":true,"origin":"","legend":"Diagnostic value of IL1RN in PTC. (A) Comparison of IL1RN mRNA expression between PTC and normal tissues based on data from TCGA. (B) Diagnostic efficacy of IL1RN as shown by the ROC curve. (C) Comparison of immunohistochemical images indicating IL1RN expression in PTC and normal thyroid tissues. (D) Kaplan–Meier curve of the progression-free survival (PFS) of the H-IL1RN group and L-IL1RN group.\n*P\u003c0.05, ** P\u003c0.01, *** P\u003c0.001, **** P\u003c0.0001 here and in the following figures.\n","description":"","filename":"Figure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/Figure1.tif"},{"id":1341217,"identity":"b2a5d064-e036-45ae-af82-e5ea0d86eace","added_by":"auto","created_at":"2020-06-16 15:46:50","extension":"tif","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1532821,"visible":true,"origin":"","legend":"Potential mechanisms of IL1RN in PTC. (A) Genes highly correlated with IL1RN identified by Pearson correlation analysis in the TCGA cohort. (B) Heatmaps showing the top 50 genes positively and (C) negatively correlated with IL1RN in the TCGA cohort. (D) PPI of the top 100 significantly correlated genes. (E) GO biological process terms and (F) KEGG pathways significantly enriched in genes coexpressed with IL1RN in the TCGA cohort.","description":"","filename":"Figure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/Figure2.tif"},{"id":1341218,"identity":"74f38dbb-2624-462d-a7e0-53c854d0969b","added_by":"auto","created_at":"2020-06-16 15:46:50","extension":"tif","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":878317,"visible":true,"origin":"","legend":"IL1RN is closely related to immunity in PTC. ESTIMATE analysis of (A) stromal scores, (B) immune scores, (C) ESTIMATE scores, and (D) tumor purity in the L-IL1RN and H-IL1RN groups. (E) TIMER analysis of the purity-corrected partial Spearman correlations between the expression of IL1RN and the infiltration of six types of immune cells in the TCGA cohort. (F) Correlation analysis of the expression of IL1RN and 28 types of TILs in various human cancers by TISIDB. (G) Correlation analysis of the expression of IL1RN and the levels of chemokines in various human cancers by TISIDB.","description":"","filename":"Figure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/Figure3.tif"},{"id":1341219,"identity":"1933b891-565f-44c5-9a5e-8f5ba3926a76","added_by":"auto","created_at":"2020-06-16 15:46:50","extension":"tif","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":715926,"visible":true,"origin":"","legend":"Methylation of IL1RN in PTC. (A) IL1RN methylation levels were compared between PTC and normal tissues. (B) Correlation analysis between IL1RN methylation and IL1RN expression in PTC. (C) Correlation analysis between IL1RN methylation and tumor purity in PTC. IL1RN methylation level among patients with different (D) clinical stages, (E) T classifications, (F) N classifications, and (G) histological types of PTC. (H) GO biological process terms and (I) KEGG pathways significantly altered by IL1RN methylation in the TCGA cohort.","description":"","filename":"Figure4.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/Figure4.tif"},{"id":1341220,"identity":"9921cbee-4a04-4816-bb73-592d6b52428a","added_by":"auto","created_at":"2020-06-16 15:46:50","extension":"tif","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":205275,"visible":true,"origin":"","legend":"(A-D) mRNA expression of IL1RN in 4 GEO verification cohorts (GSE3467, GSE33630, GSE58545, and GSE60542). (J-O) ROC curve showing the diagnostic value of IL1RN expression in the verification cohorts.","description":"","filename":"Figure5.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/Figure5.tif"},{"id":1341221,"identity":"3cfea02a-5fc5-46a0-b469-d52671069c4a","added_by":"auto","created_at":"2020-06-16 15:46:51","extension":"tif","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1600424,"visible":true,"origin":"","legend":"Generalizability of differences in IL1RN expression in different cancers. (A) Comparison of IL1RN mRNA expression between cancer and paracancerous tissues in different cancers. (B) Association between TREM-1 expression and OS in different human cancers. K-M survival analysis between the L-IL1RN and H-IL1RN groups in (C) the pancancer, (D) KIRC, (E) LGG, (F) PAAD, and (G) UCEC cohorts.","description":"","filename":"Figure6.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/Figure6.tif"},{"id":13540500,"identity":"51431a8c-6f2d-4c76-8afc-ae8179bd32e9","added_by":"auto","created_at":"2021-09-17 01:47:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9851825,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/55a1317b-ecf2-4f20-8c29-9f4e94d2ec38.pdf"},{"id":1341223,"identity":"2628c2d6-ea2f-4e42-baab-474fc4bfc738","added_by":"auto","created_at":"2020-06-16 15:46:51","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1657758,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS1.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/FigureS1.tif"},{"id":1341224,"identity":"fcb84b3e-2bf9-4d89-8f26-a0d67d77d9ea","added_by":"auto","created_at":"2020-06-16 15:46:52","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12218126,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS2.tif","url":"https://assets-eu.researchsquare.com/files/rs-35109/v1/FigureS2.tif"}],"financialInterests":"","formattedTitle":"Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods","fulltext":[{"header":"1 Introduction","content":" \u003cp\u003eThyroid carcinoma (THCA) is the most common endocrine malignancy worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incidence of THCA has increased sharply over the past 3 decades [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Papillary thyroid carcinoma (PTC) is the major subtype of THCA, accounting for more than 90% of cases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The clinical course of PTC is generally indolent, and the cancer-specific mortality of PTC is low compared to that of other cancers [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, the incidence of cervical lymph node metastasis is high, which leads to local recurrence and poor prognosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The main task for the future is to identify high-risk patients and to give them appropriate treatment and care [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, further studies are required to explore the underlying mechanisms of tumorigenesis as well as identify additional biomarkers that predict prognosis and serve as therapeutic targets.\u003c/p\u003e \u003cp\u003eThe interleukin-1 (IL-1) family of cytokines are the most effective molecules in the innate immune system [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. IL-1 receptor antagonist (IL1RN) was initially found as a natural antagonist of IL-1[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. IL1RN is structurally related to IL-lα and IL-lβ but binds to IL-1 receptors on various target cells without inducing any discernible biological responses [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The balance between IL1RN and IL-1 plays a crucial role in many diseases, including cancer [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. IL1RN has been studied in several cancers, including prostate carcinoma [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], cervical carcinoma [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], gastric carcinoma [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], bronchogenic carcinoma [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], endometrial cancer [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], lung cancer [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], ovarian cancer [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], oral malignancies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], leukemia [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and other cancers.\u003c/p\u003e \u003cp\u003eTwo structural variants of IL1RN have been described: the soluble extracellular form (sIL-1ra) and the intracellular form (icIL-1ra) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Niedzwiecki, S. and colleagues assayed the serum levels of IL1RN in thyroid cancer patients. They measured preoperative IL1RN serum levels of patients with thyroid cancer, and the results showed that the serum concentrations of sIL-1ra were significantly higher in anaplastic carcinoma (ATC) and follicular carcinoma (FTC) patients [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. To the best of our knowledge, no reports have been published to date concerning IL1RN expression in thyroid tissue. The objective of this study was to investigate the expression of IL1RN in normal and papillary thyroid cancer tissues by performing bioinformatics analysis to elucidate its possible role in tumor progression.\u003c/p\u003e "},{"header":"2 Materials And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Expression level analysis\u003c/h2\u003e \u003cp\u003eThe cohort that comprised 512 PTC and 58 normal thyroid samples was obtained from The Cancer Genome Atlas (TCGA) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://tcga-data.nci.nih.gov/tcga/\u003c/span\u003e\u003c/span\u003e). The clinical data, normalized RNA expression data, DNA methylation data and simple nucleotide variation data were downloaded from the TCGA data portal.\u003c/p\u003e \u003cp\u003eThe gene expression profiles of four independent datasets (GSE3467, GSE33630, GSE58545, and GSE60542) were downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/geo/\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe immunohistochemical staining images of IL1RN in PTC and normal tissues were obtained from The Human Protein Atlas (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.proteinatlas.org\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Diagnostic and prognostic value analysis\u003c/h2\u003e \u003cp\u003eROC curves were plotted, and the area under the ROC curve was calculated using the ROCR package in R. The patients were divided into a high IL1RN expression group (H-IL1RN) and a low IL1RN expression group (L-IL1RN) according to the best matched value for the survival analysis. Kaplan-Meier survival curves were generated by the R survival package. The primary end point of the study was progression-free survival (PFS). Univariate and multivariate analyses were performed using the Cox regression model to assess the significance of various variables to survival. A chi-square test was performed to compare the clinical characteristics between the H-IL1RN group and the L-IL1RN group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Gene functional enrichment analysis\u003c/h2\u003e \u003cp\u003eWe identified the genes that were significantly positively or negatively correlated with IL1RN using the LinkedOmics website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.linkes.org/\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe top 50 positively correlated genes and the top 50 negatively correlated genes were selected to build the heatmaps.\u003c/p\u003e \u003cp\u003eThese genes were inputted into the GO and KEGG websites to obtain the enriched GO terms and significant KEGG pathways. GO function annotation analysis was performed based on the GO database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://geneontology.org/page/go-database\u003c/span\u003e\u003c/span\u003e), and KEGG pathway annotation analysis was performed based on the KEGG database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.kegg.jp/kegg/ko.html\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe protein-protein interaction (PPI) network with a confidence\u0026thinsp;\u0026gt;\u0026thinsp;0.7 was constructed using STRING (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://string-db.org\u003c/span\u003e\u003c/span\u003e) and CytoScape version 3.7.2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Tumor immunology analysis\u003c/h2\u003e \u003cp\u003eESTIMATE used the single-sample gene-set enrichment analysis (ssGSEA) score to quantify the enrichment levels of immune gene signatures in tumors. The stromal, immune and ESTIMATE scores of TCGA PTC samples were computed using ESTIMATE, and then the tumor purity of each sample was inferred.\u003c/p\u003e \u003cp\u003eThe Tumor Immune Estimation Resource (TIMER) web server (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cistrome.shinyapps.io/timer/\u003c/span\u003e\u003c/span\u003e), a comprehensive analytic web tool, was used to analyze the correlation of IL1RN with infiltration of immune cells, including B cells, CD8\u0026thinsp;+\u0026thinsp;T cells, CD4\u0026thinsp;+\u0026thinsp;T cells, macrophages, neutrophils and dendritic cells (DCs).\u003c/p\u003e \u003cp\u003eWe used TISIDB (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://cis.hku.hk/TISIDB/\u003c/span\u003e\u003c/span\u003e), a web portal for investigation of tumor and immune system interaction, to determine the Spearman correlation between IL1RN expression and 28 TIL types, chemokines, immune-activating cytokines, immunosuppressive cytokines, major histocompatibility complex (MHC) molecules, and chemokine receptors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Methylation-related analysis\u003c/h2\u003e \u003cp\u003eDNA methylation data were downloaded from the data portal of TCGA (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://portal.gdc.cancer.gov/\u003c/span\u003e\u003c/span\u003e), and the DNA methylation levels of the PTC and control groups were then compared. Spearman correlation analysis was conducted to examine the associations between the methylation density and gene expression and between the methylation density and tumor purity. Additionally, we analyzed the correlation between IL1RN expression and the methylation level of each CpG site using the Spearman correlation test. The analysis of the relationship between methylation and the clinical characteristics and the GO and KEGG analyses were performed using linkedOmics.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Pancancer analysis\u003c/h2\u003e \u003cp\u003eThe pancancer expression and survival analysis of IL1RN was performed using the online software Gene Expression Profiling Interactive Analysis (GEPIA) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gepia.cancer-pku.cn/\u003c/span\u003e\u003c/span\u003e). We used TISIDB to analyze the relationships between IL1RN expression and overall survival (OS) in pancancer. Kaplan-Meier (K-M) curves were generated for pancancer using the TCGA cohort data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Related mutant gene analysis\u003c/h2\u003e \u003cp\u003eThe analysis of the relationship between IL1RN expression and PTC mutations was performed by linkedOmics. The IL1RN expression level was further compared between the groups with wild-type and mutant versions of BRAF, NRAS and HRAS.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8 Statistical analysis\u003c/h2\u003e \u003cp\u003eThe \u003cem\u003et\u003c/em\u003e-test and Mann-Whitney U test were used for comparisons between two groups. The chi-square test was used to assess the differences in clinical parameters between the L-IL1RN and H-IL1RN groups. The Pearson and Spearman methods were used for correlation analysis. The log-rank method was used to calculate the significant \u003cem\u003ep\u003c/em\u003e-values related to survival. R software (v3.6.0) and SPSS version 25.0 software were used for statistical processing. Visualization of data was performed with GraphPad Prism V.8.0 and R software. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/div\u003e "},{"header":"3 Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 The differential expression and diagnostic value of IL1RN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe expression levels of IL1RN were initially analyzed in the TCGA cohort consisting of 512 PTC samples and 58 normal samples (Figure 1A). Furthermore, expression data from four independent PTC cohorts obtained from the Gene Expression Omnibus (GEO) (GSE3467, GSE33630, GSE58545, and GSE60542) were employed for validation (Figure 5A-D). Both the GEO and TCGA patient cohorts had significantly higher IL1RN mRNA expression in PTC tissues than in normal tissues (P\u0026lt;0.05). Elevated levels of IL1RN protein expression were observed in PTC tissues compared with those in normal tissues by immunohistochemistry performed using the IL1RN antibody CAB9633. (Figure 1C)\u003c/p\u003e\n\u003cp\u003eROC curves were constructed to evaluate the diagnostic value of IL1RN for PTC. The area under the ROC curve of the TCGA cohort was 0.7084 (Figure 1B) and that of each GEO cohort was 0.9753, 0.7279, 0.8868, and 0.8384, respectively. (Figure 5E-H) These results suggest the good positive diagnostic value of IL1RN for PTC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Prognostic value\u0026nbsp;and clinical significance of IL1RN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PTC samples from the TCGA cohort were divided into two groups according to the IL1RN expression level: the high-expression group (H-IL1RN) (n\u0026thinsp;=\u0026thinsp;116) and the low-expression group (L-IL1RN) (n\u0026thinsp;=\u0026thinsp;385). Differences in progression-free survival (PFS) between the two groups were analyzed by Kaplan-Meier analysis. (Figure 1D)\u0026nbsp;The results showed that patients with high IL1RN expression had significantly shorter PFS than those with low expression (P=0.0034). However, the data for the multivariate analysis by the Cox regression model suggested that IL1RN expression was not a significant independent prognostic risk indicator for PTC (hazard ratio, 1.033; 95% confidence interval, 0.999\u0026minus;1.068, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table 1). Age was an independent predictor of poor prognosis (P＜0.05).\u003c/p\u003e\n\u003cp\u003eTo examine the clinical significance of IL1RN in PTC, the relationship between the expression level of IL1RN and clinical characteristics was investigated by the chi-square test (Table 2). The results\u0026nbsp;suggested that IL1RN expression was significantly associated with age, clinical stage, N stage, T stage, pathologic type, BRAF mutations and RAS mutations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Gene coexpression and pathway enrichment analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified the genes that are significantly positively or negatively related to IL1RN. The result is presented as a volcano plot (Figure 2A).\u0026nbsp;Red and green colors indicate a positive and negative correlation, respectively. The top 50 positively (Figure 2B) or negatively (Figure 2C) correlated genes are depicted by heatmaps. In addition, 2 hub genes (CCL20 and FN1) were identified from the protein\u0026ndash;protein interaction (PPI) network (Figure 2D).\u003c/p\u003e\n\u003cp\u003eGO enrichment analysis revealed that the identified genes were mainly enriched for the GO biological process terms \u0026ldquo;neutrophil mediated immunity\u0026rdquo;, \u0026ldquo;positive regulation of cytokine production\u0026rdquo;, \u0026ldquo;adaptive immune response\u0026rdquo; and \u0026ldquo;immune response-regulating signalling pathway\u0026rdquo; (Figure 2E). Further KEGG enrichment analysis suggested that the identified genes were mainly involved in pathways associated with \u0026ldquo;cell adhesion molecules (CAMs)\u0026rdquo;, \u0026ldquo;cytokine-cytokine receptor interaction\u0026rdquo;, and \u0026ldquo;phagosome\u0026rdquo; (Figure 2F).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Immune-related analysis of IL1RN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing ESTIMATE, the association between IL1RN expression and immune infiltrates was analyzed. We found that the H-IL1RN group showed a higher immune score (Figure 3B) and ESTIMATE score (Figure 3C) and lower tumor purity (Figure 3D) than the L-IL1RN group. No significant difference in the stromal score was found between the two groups (Figure 3A). The correlations between the IL1RN expression level and the infiltration of six immune cell types in PTC were estimated. The results demonstrated that the expression of IL1RN was found to be significantly correlated with the infiltration of immune cells, especially neutrophils and dendritic cells (Figure 3E). Correlations between IL1RN expression and 28 TIL types (Figure 3F), chemokines (Figure 3G), immune-activating cytokines (Figure S2A), immunosuppressive cytokines (Figure S2B), MHC molecules (Figure S2C),\u0026nbsp;and chemokine receptors (S2D) in pancancer are shown in heatmaps. The correlation analysis results showed a good correlation between IL1RN expression and immune-related molecules.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Methylation-related analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data showed that the degree of IL1RN DNA methylation was higher in carcinoma tissues than in normal tissues (P\u0026lt;0.0001) (Figure 4A). To further determine the role of methylation, we performed a correlation analysis between the DNA methylation levels of IL1RN and the expression levels of IL1RN. As expected, DNA methylation was negatively correlated with IL1RN expression (R=-0.600, P=2.29e-50) (Figure 4B). Tumor purity was significantly positively associated with IL1RN methylation (R=0.447, P=7.49e-32) (Figure 4C). Patients with an advanced clinical stage (Figure 4D), advanced T stage (Figure 4E) and lymph node metastasis (Figure 4F) tended to have decreased IL1RN methylation levels. In the pathological subtype of PTC, the tall cell type variant of PTC had the lowest degree of methylation, followed by the classical type, and the follicular variant of PTC had the highest degree of methylation (Figure 4G). To further explore the associated functional changes in IL1RN methylation, GO (Figure 4I) and KEGG (Figure 4F) enrichment analyses were performed. The results showed that methylated IL1RN had the opposite effect of IL1RN. Furthermore, the most significant methylation sites are shown in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6 Pancancer analysis of IL1RN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed the IL1RN expression levels in different kinds of tumors via the GEPIA platform (Figure 6A). The results showed that the expression levels of IL1RN varied greatly in different cancer types. Of the 33 cancer types tested, 12 cancer types\u0026nbsp;were associated with significantly increased IL1RN expression. Subsequently, the relationship between IL1RN and OS in pancancer was investigated (Figure 6B). Kaplan-Meier survival curves for the high IL1RN expression group (4745 patients) and low IL1RN expression group (4750 patients) indicated that increased IL1RN expression was associated with a shorter survival time in pancancer (HR=1.6, P\u0026lt;0.0001) (Figure 6C). The results showed that increased IL1RN expression levels were significantly associated with shorter OS in kidney renal clear cell carcinoma (KIRC) (Figure 6D), brain lower grade glioma (LGG) (Figure 6E), pancreatic\u0026ensp;adenocarcinoma (PADD) (Figure 6F) and uterine corpus endometrial carcinoma (UCEC) (Figure 6G).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.7 Related mutant gene analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analysis of the relationship between IL1RN expression and PTC mutations was performed by linkedOmics (Figure S1A). The IL1RN expression level was further compared between the groups with wild-type and mutant variants of BRAF, NRAS and HRAS (Figure S1B-D). The expression of IL1RN was significantly higher in PTC with the BRAF mutant than in PTC with the wild type (Figure S1B). However, mutated NRAS (Figure S1C) and mutated HRAS (Figure S1D) were correlated with decreased IL1RN expression.\u003c/p\u003e"},{"header":"4 Discussion","content":" \u003cp\u003eIn this study, we first revealed high IL1RN expression in PTC tissues and its diagnostic and prognostic value by integrated bioinformatics analysis. To further explore the potential function of IL1RN, we identified genes related to IL1RN expression, and functional enrichment analyses were conducted. The results of the KEGG pathway and GO analyses revealed the significant enrichment of genes in immune-related pathways. Our work further demonstrated that high IL1RN expression was significantly associated with decreased tumor purity and increased immune infiltration. Through methylation-related analysis, we determined that DNA methylation might be a regulatory mechanism of IL1RN. In addition, the analysis of the relationship between IL1RN expression and PTC mutations showed that high IL1RN expression was associated with mutated BRAF, wild-type NRAS and wild-type HRAS. Finally, IL1RN shows superior prognostic value for various cancers according to the pancancer analysis.\u003c/p\u003e \u003cp\u003eNiedzwiecki et al [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] revealed that the serum levels of IL1RN were upregulated in patients with ATC and PTC, but no statistically significant difference was found in PTC. We found that the expression of IL1RN was increased in PTC tissues compared with that in normal tissues in 1 TCGA cohort and 4 GEO cohorts and suggested that IL1RN might be used as a potential diagnostic biomarker in PTC. Our results were consistent with those of previous reports on the upregulation of IL1RN in cervical carcinoma [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], gastric cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], lung cancer [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and endometrial cancer tissues [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These findings are also basically consistent with the results of our pancancer study. In contrast to these findings, IL1RN exhibited low expression in oral squamous cell carcinomas (OSCCs) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe results of this study showed the value of IL1RN as a clinical biomarker in PTC and emphasized its potential as a prognostic biomarker in PTC patients. PTC patients with high IL1RN expression had decreased PFS compared to those with low IL1RN expression. Furthermore, high expression of IL1RN was significantly correlated with clinical stage, lymph node metastasis and pathological type. Various studies have highlighted the significant association between IL1RN expression and poor cancer prognosis; however, the results of these studies are conflicting. Van Le et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] revealed that there was a significant correlation between the stage of endometrioid carcinoma and the expression of IL1RN. In a study of colorectal cancer, serum IL1RN levels were correlated with tumor size, local and distant metastasis and vascular infiltration [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. An increase in IL1RN expression was correlated significantly with lymph node and liver metastases in gastric carcinoma [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In contrast, low levels of IL1RN have been associated with increased disease severity in myeloma [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], colorectal cancer [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and prostate cancer [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe underlying mechanism of IL1RN in cancer development and progression is complicated and unclear. In this study, functional enrichment analysis of genes coexpressed with IL1RN showed that IL1RN participates in immune-related biological processes. Consistent with our findings, previous studies have focused on the role of IL1RN in tumor immunity. A study of gastric carcinoma [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] pointed out that on the one hand, IL1RN may promote tumor growth via the impairment of cellular immunity; on the other hand, IL1RN enables malignant cells to escape host immune responses. Smith, D. R. et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] revealed that increased IL1RN in bronchogenic carcinoma is not accompanied by increased IL-1β activity. The altered balance of IL1RN and IL-1β may result in impaired immune surveillance and cytotoxic activity. An experimental study of human glioblastoma cells showed that IL1RN secreted by tumor cells can counteract IL-1 function, which represents a potential escape mechanism that supports cancer growth [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In our study, IL1RN was significantly positively correlated with lymph node metastasis and tumor stage, so we speculated that IL1RN might also promote tumor aggressiveness and poor prognosis through immune-related mechanisms in PTC.\u003c/p\u003e \u003cp\u003eIL1RN is an endogenous natural antagonist of IL-1[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], so the discovery of the interaction between IL1RN and IL-1 family molecules is a breakthrough in exploring the function of IL1RN. ONOZAKI et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] reported that IL-1 is a cytocidal factor against several tumor cell lines. IL-1 may enhance cytotoxic T cell activity [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], the tumoricidal capacities of natural killer (NK) cells [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and monocyte-mediated cytotoxicity [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Because IL-1 is critical for tumor immunity, elevation of IL1RN expression may result in a general environment favourable to tumor cells and enhance the metastatic and recurrence potential of tumors by changing local IL-1-dependent pathways.\u003c/p\u003e \u003cp\u003eIL-1β has been reported as an anticancer factor that acts to suppress proliferation and reduce the invasive potential of human PTC cells [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. sIL-1ra has been shown to block IL-1 function by binding to IL-1 receptors at the cell membrane level [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. IcIL-1ra is postulated to inhibit intracellular IL-1 activity [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, whether IL1RN can block the function of IL-1 and inhibit the anticancer effect of IL-1β in PTC is worth further study.\u003c/p\u003e \u003cp\u003eIn our study, IL1RN showed a significant positive correlation with immune cells, which may be because a variety of immune cells can produce IL1RN through the stimulation of cytokines. Neutrophils produce IL1RN in response to granulocyte/macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. IL-4 and IL-10 have been reported to increase the production of IL1RN by human monocytes [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Yanagawa, H.et, al. reported that IL-13 increases IL1RN production by human alveolar macrophages [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. It was reported that the apoptotic cell death of monocytes was enhanced by administration of recombinant IL1RN [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Our study also showed a significant correlation between IL1RN expression and various cytokines, which implied that IL1RN may play a complex role in tumor immunity.\u003c/p\u003e \u003cp\u003eOur study suggests that methylation is a pretranscriptional regulatory mechanism for IL1RN. The methylation level of IL1RN was negatively correlated with its expression level and was also correlated with the disease stage, lymph node metastasis, and pathological type.\u003c/p\u003e \u003cp\u003eIL1RN is likely to be a potential biomarker associated with the diagnosis and prognosis of PTC. However, although the diagnostic value, prognostic value and molecular functions of IL1RN in PTC have been analyzed through bioinformatics methods, the conclusions have not yet been confirmed by experiments. Therefore, further research is necessary to explore the role of IL1RN in PTC and the pharmacological value of IL1RN as a therapeutic target.\u003c/p\u003e "},{"header":"5 Conclusions","content":"\u003cp\u003eIL1RN is a good prognostic and diagnostic biomarker of PTC. IL1RN may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of IL1RN expression and biological function. Additionally, IL1RN showed broad prognostic value in an analysis of a pancancer cohort.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e1 Ethics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2 Consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3 Availability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analysed during the current study are available in The Cancer Genome Atlas (TCGA) (https://tcga-data.nci.nih.gov/tcga/) or the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4 Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5 Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by National Natural Science Foundation of China (81600602).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6 Authors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZX designed the analytical strategies, performed data analyses and wrote the manuscript. XL performed data analysis and wrote the manuscript. YZH, SW, SYW, JS, YCH, YL and SJX performed data analysis. JZ conceived the research and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7 Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the public databases including TCGA and GEO for their contributions to human medicine.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable style=\"margin-left:17.85pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style='font-size: 16px; line-height: 200%; font-family: \"Times New Roman\", serif; color: rgb(0, 0, 0);'\u003eIL1RN\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003einterleukin-1 receptor antagonist\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ePTC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003epapillary thyroid carcinoma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eTCGA\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eThe Cancer Genome Atlas\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eOS\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003eoverall survival\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eGEPIA\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eGene Expression Profiling Interactive Analysis\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ePFS\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eprogression-free survival\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eTHCA\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ethyroid carcinoma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eIL-1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003einterleukin-1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003esIL-1ra\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ethe soluble extracellular form of IL1RN\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eicIL-1ra\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ethe intracellular form of IL1RN\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eATC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eanaplastic carcinoma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eFTC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003efollicular carcinoma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eNCBI\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ethe National Center for Biotechnology Information\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eGEO\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eGene Expression Omnibus\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eH-IL1RN\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ehigh IL1RN expression group\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eL-IL1RN\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003elow IL1RN expression group\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ePPI\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003eprotein-protein interaction\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003essGSEA\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;text-indent:24.0pt;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003esingle-sample gene-set enrichment analysis\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eTIMER\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003eTumor Immune Estimation Resource\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eDCs\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003edendritic cells\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eMHC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003emajor histocompatibility complex\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eK-M\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003eKaplan\u003c/span\u003e\u003cspan style=\"font-size:16px;line-height:200%;\"\u003e‐\u003c/span\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eMeier\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eCAMs\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003ecell adhesion molecules\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eKIRC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003ekidney renal clear cell carcinoma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eLGG\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003elower grade glioma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ePADD\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003epancreatic\u0026ensp;adenocarcinoma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eUCEC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003euterine corpus endometrial carcinoma\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eOSCCs\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003eoral squamous cell carcinomas\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eNK\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003enatural killer\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eGM-CSF\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003egranulocyte/macrophage colony stimulating factor\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eTNF-\u0026alpha;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201.9pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;line-height:200%;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;'\u003etumor necrosis factor-\u0026alpha;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.\u003c/li\u003e\n\u003cli\u003eSeib CD, Sosa JA. Evolving Understanding of the Epidemiology of Thyroid Cancer. Endocrinol Metab Clin North Am. 2019;48(1):23-35.\u003c/li\u003e\n\u003cli\u003eSiegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30.\u003c/li\u003e\n\u003cli\u003eCancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676-90.\u003c/li\u003e\n\u003cli\u003eHaugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133.\u003c/li\u003e\n\u003cli\u003eRaue F, Frank-Raue K. Thyroid Cancer: Risk-Stratified Management and Individualized Therapy. Clin Cancer Res. 2016;22(20):5012-21.\u003c/li\u003e\n\u003cli\u003eSims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010;10(2):89-102.\u003c/li\u003e\n\u003cli\u003eArend WP. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest. 1991;88(5):1445-51.\u003c/li\u003e\n\u003cli\u003eArend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998;16:27-55.\u003c/li\u003e\n\u003cli\u003eArend WP. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 2002;13(4-5):323-40.\u003c/li\u003e\n\u003cli\u003eRicote M, Garcia-Tunon I, Bethencourt FR, Fraile B, Paniagua R, Royuela M. Interleukin-1 (IL-1alpha and IL-1beta) and its receptors (IL-1RI, IL-1RII, and IL-1Ra) in prostate carcinoma. Cancer. 2004;100(7):1388-96.\u003c/li\u003e\n\u003cli\u003eHsieh TC, Chiao JW. Growth modulation of human prostatic cancer cells by interleukin-1 and interleukin-1 receptor antagonist. Cancer Lett. 1995;95(1-2):119-23.\u003c/li\u003e\n\u003cli\u003eFujiwaki R, Iida K, Nakayama K, Kanasaki H, Hata K, Katabuchi H, et al. Clinical significance of interleukin-1 receptor antagonist in patients with cervical carcinoma. Gynecol Oncol. 2003;89(1):77-83.\u003c/li\u003e\n\u003cli\u003eIizuka N, Hazama S, Hirose K, Abe T, Tokuda N, Fukumoto T, et al. Interleukin-1 receptor antagonist mRNA expression and the progression of gastric carcinoma. Cancer Lett. 1999;142(2):179-84.\u003c/li\u003e\n\u003cli\u003eSmith DR, Kunkel SL, Standiford TJ, Chensue SW, Rolfe MW, Orringer MB, et al. The production of interleukin-1 receptor antagonist by human bronchogenic carcinoma. Am J Pathol. 1993;143(3):794-803.\u003c/li\u003e\n\u003cli\u003eVan Le L, Haskill S, Jaffe GJ, Fowler WC, Jr. Expression of interleukin-1 and interleukin-1 receptor antagonists in endometrial cancer. Gynecol Oncol. 1991;42(2):161-4.\u003c/li\u003e\n\u003cli\u003eYanagawa H, Yano S, Haku T, Ohmoto Y, Sone S. Interleukin-1 receptor antagonist in pleural effusion due to inflammatory and malignant lung disease. Eur Respir J. 1996;9(6):1211-6.\u003c/li\u003e\n\u003cli\u003eMustea A, Pirvulescu C, Konsgen D, Braicu EI, Yuan S, Sun P, et al. Decreased IL-1 RA concentration in ascites is associated with a significant improvement in overall survival in ovarian cancer. Cytokine. 2008;42(1):77-84.\u003c/li\u003e\n\u003cli\u003eShiiba M, Saito K, Yamagami H, Nakashima D, Higo M, Kasamatsu A, et al. Interleukin-1 receptor antagonist (IL1RN) is associated with suppression of early carcinogenic events in human oral malignancies. Int J Oncol. 2015;46(5):1978-84.\u003c/li\u003e\n\u003cli\u003eWetzler M, Kurzrock R, Estrov Z, Kantarjian H, Gisslinger H, Underbrink MP, et al. Altered levels of interleukin-1 beta and interleukin-1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates. Blood. 1994;84(9):3142-7.\u003c/li\u003e\n\u003cli\u003eNiedzwiecki S, Stepien T, Kuzdak K, Stepien H, Krupinski R, Seehofer D, et al. Serum levels of interleukin-1 receptor antagonist (IL-1ra) in thyroid cancer patients. Langenbecks Arch Surg. 2008;393(3):275-80.\u003c/li\u003e\n\u003cli\u003eGherardi RK, Belec L, Soubrier M, Malapert D, Zuber M, Viard JP, et al. Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. Blood. 1996;87(4):1458-65.\u003c/li\u003e\n\u003cli\u003eIwagaki H, Hizuta A, Tanaka N. Interleukin-1 receptor antagonists and other markers in colorectal cancer patients. Scand J Gastroenterol. 1997;32(6):577-81.\u003c/li\u003e\n\u003cli\u003eParekh DJ, Ankerst DP, Baillargeon J, Higgins B, Platz EA, Troyer D, et al. Assessment of 54 biomarkers for biopsy-detectable prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007;16(10):1966-72.\u003c/li\u003e\n\u003cli\u003eOnozaki K, Matsushima K, Aggarwal BB, Oppenheim JJ. Human interleukin 1 is a cytocidal factor for several tumor cell lines. J Immunol. 1985;135(6):3962-8.\u003c/li\u003e\n\u003cli\u003eYip I, Pang XP, Berg L, Hershman JM. Antitumor actions of interferon-gamma and interleukin-1 beta on human papillary thyroid carcinoma cell lines. J Clin Endocrinol Metab. 1995;80(5):1664-9.\u003c/li\u003e\n\u003cli\u003eHannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990;343(6256):336-40.\u003c/li\u003e\n\u003cli\u003eMosley B, Urdal DL, Prickett KS, Larsen A, Cosman D, Conlon PJ, et al. The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. J Biol Chem. 1987;262(7):2941-4.\u003c/li\u003e\n\u003cli\u003eDvorkin T, Song X, Argov S, White RM, Zoller M, Segal S, et al. Immune phenomena involved in the in vivo regression of fibrosarcoma cells expressing cell-associated IL-1alpha. J Leukoc Biol. 2006;80(1):96-106.\u003c/li\u003e\n\u003cli\u003eVoronov E, Weinstein Y, Benharroch D, Cagnano E, Ofir R, Dobkin M, et al. Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin 1alpha expression. Cancer Res. 1999;59(5):1029-35.\u003c/li\u003e\n\u003cli\u003eOelmann E, Kraemer A, Serve H, Reufi B, Oberberg D, Patt S, et al. Autocrine interleukin-1 receptor antagonist can support malignant growth of glioblastoma by blocking growth-inhibiting autocrine loop of interleukin-1. Int J Cancer. 1997;71(6):1066-76.\u003c/li\u003e\n\u003cli\u003eIto H, Miki C. Profile of circulating levels of interleukin-1 receptor antagonist and interleukin-6 in colorectal cancer patients. Scand J Gastroenterol. 1999;34(11):1139-43.\u003c/li\u003e\n\u003cli\u003eFurukawa Y, Kikuchi J, Terui Y, Kitagawa S, Ohta M, Miura Y, et al. Preferential production of interleukin-1 beta over interleukin-1 receptor antagonist contributes to proliferation and suppression of apoptosis in leukemic cells. Jpn J Cancer Res. 1995;86(2):208-16.\u003c/li\u003e\n\u003cli\u003eMcColl SR, Paquin R, Menard C, Beaulieu AD. Human neutrophils produce high levels of the interleukin 1 receptor antagonist in response to granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. J Exp Med. 1992;176(2):593-8.\u003c/li\u003e\n\u003cli\u003ede Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174(5):1209-20.\u003c/li\u003e\n\u003cli\u003eLovett D, Kozan B, Hadam M, Resch K, Gemsa D. Macrophage cytotoxicity: interleukin 1 as a mediator of tumor cytostasis. J Immunol. 1986;136(1):340-7.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:justify;font-size:14px;font-family:DengXian;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eTable 1\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"border: none;width:492.85pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:105.3pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid black 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:16.15pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eVariables\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:201.7pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:16.15pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eUnivariate analysis\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:185.85pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:16.15pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eMultivariate analysis\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:149.85pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.15pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eHazard ratio (95%CI)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:51.85pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.15pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eP value\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:139.55pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.15pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eHazard ratio (95%CI)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:46.3pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:16.15pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eP value\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:105.3pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eAge(y\u003c/span\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026ge;55/\u0026lt;55)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e3.958(2.274\u0026minus;6.891)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139.55pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e2.582(1.312\u0026minus;5.083)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.3pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e0.006\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:105.3pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eGender(male/female)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e1.471(0.834\u0026minus;2.592)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e0.182\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139.55pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e1.098(0.604\u0026minus;1.997)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.3pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e0.758\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:105.3pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eClinical stage\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e1.736(1.380\u0026minus;2.185)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139.55pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e1.301(0.968\u0026minus;1.748)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.3pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e0.081\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:105.3pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003eRadiation therapy\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e1.305(0.728\u0026minus;2.343)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.85pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e0.372\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139.55pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e1.205(0.651\u0026minus;2.233)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.3pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e0.553\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:105.3pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eIL1RN\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149.85pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e1.058(1.024\u0026minus;1.093)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.85pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15.75pt;vertical-align: top;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n 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0);\"\u003e\u003cspan style=\"font-size: 13px; font-family: Helvetica, sans-serif;\"\u003e0.059\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:justify;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:justify;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif;\"\u003eTable 2\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border: none;width:343.0pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:97.0pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eClinical parameters\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eL-IL1RN(n=385,%)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:103.7pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eH-IL1RN(n=116,%)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:45.3pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eP-value\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97pt;border: none;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eAge(y)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;border:none;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:103.7pt;border:none;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:45.3pt;border:none;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026lt;55\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e261(67.8)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:103.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e73(62.9)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:45.3pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e0.330\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e\u0026ge;55\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e124(32.2)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:103.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e43(37.1)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eGender\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:103.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:45.3pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eFemale\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e282(73.2)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:103.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp 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style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eT3\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e116(30.1)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:103.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e54(47.4)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97pt;padding: 0in 5.4pt;height: 15.75pt;vertical-align: bottom;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eT4\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp 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style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:left;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eMutation\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:97.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:center;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003e58(15.7)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:103.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp 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5.4pt;height:15.75pt;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:17.85pt;text-align:justify;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;text-align:justify;font-size:14px;font-family:DengXian;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif;\"\u003eTable 3\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width:279.0pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:96.0pt;border-top:solid windowtext 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style='font-size:13px;font-family:\"Arial\",sans-serif;'\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IL1RN, papillary thyroid carcinoma, diagnostic biomarker, prognostic biomarker, cancer immunity, IL-1","lastPublishedDoi":"10.21203/rs.3.rs-35109/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-35109/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Interleukin-1 receptor antagonist (IL1RN) has been reported as a biomarker of many cancers. However, the biological function of IL1RN in papillary thyroid carcinoma (PTC) remains undetermined.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We obtained IL1RN expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and IL1RN methylation analysis were performed via LinkedOmics. The correlations between IL1RN and immune infiltrates were investigated via ESTIMATE, TIMER and TISIDB. We analyzed the association of IL1RN expression with pancancer overall survival (OS) via Gene Expression Profiling Interactive Analysis (GEPIA).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u0026nbsp;IL1RN showed higher expression levels and lower methylation levels in PTC tissues than in normal tissues. Higher IL1RN expression was significantly associated with shorter progression-free survival (PFS), advanced tumor stage, tumor metastasis, increased incidence of BRAF mutations, and decreased incidence of N-RAS and H-RAS mutations. Genes coexpressed with IL1RN participate primarily in immune-related pathways. IL1RN expression was positively correlated with immune infiltration, tumor progression and poor overall survival for all cancers.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u0026nbsp;\u003c/strong\u003eIL1RN is a good prognostic and diagnostic biomarker for PTC. IL1RN may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of IL1RN expression and biological function. Additionally, IL1RN was shown to have broad prognostic value in a pancancer cohort.\u003c/p\u003e","manuscriptTitle":"Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-06-16 15:46:49","doi":"10.21203/rs.3.rs-35109/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3ede4133-3a37-4208-af8c-2d0db93370f9","owner":[],"postedDate":"June 16th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":120204,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-07-22T02:37:59+00:00","versionOfRecord":{"articleIdentity":"rs-35109","link":"https://doi.org/10.1186/s12885-020-07620-8","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2020-11-25 02:37:59","publishedOnDateReadable":"November 25th, 2020"},"versionCreatedAt":"2020-06-16 15:46:49","video":"","vorDoi":"10.1186/s12885-020-07620-8","vorDoiUrl":"https://doi.org/10.1186/s12885-020-07620-8","workflowStages":[]},"version":"v1","identity":"rs-35109","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-35109","identity":"rs-35109","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}