Prognostic role of CRABP2 in lung cancer：A meta-analysis

Prognostic role of CRABP2 in lung cancer：A meta-analysis | 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 Research Article Prognostic role of CRABP2 in lung cancer：A meta-analysis Guang Yang, Qifan Yin, Wenhao Wang, Siwei Xu, Huining Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3088146/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background The prognostic value of cellular retinoic acid-binding protein 2 (CRABP2), in lung cancer patients remains to be uncertained. Therefore, our research attempted to assess the relationship between CRABP2 and survival analysis in lung cancer patients through meta-analysis. Method Related literature retrieved from Cochrane Library, Ovid, Embase, PubMed, the CNKI, and the Web of Science. The latest update of the search was May 1, 2023. The outcome indicators included as effective measures in the study were hazard ratio (HR), and 95% confidence interval (CI). The Stata 12.0 software was used to analyze the data. Results A total of 4 studies were finally enrolled in our meta-analysis. The increased plasma level of CRABP2 predicted poor OS in lung cancer patient with a combined HR of 1.14 (95% CI: 1.00–1.30), and were not associated with poor PFS with combined HR:1.15% CI: 0.63–2.09) in lung cancer patients. Conclusions Our meta-analysis found the increased plasma level of CRABP2 was associated with poor OS independently in NSCLC patients. The plasma CRABP2 level may be an indicator of biological aggressiveness of the tumor. Our research was promising regarding the feasibility and utility of plasma CRABP2 as a novel prognostic biomarker in NSCLC, and the findings warrant further investigation. Lung cancer Prognosis CRABP2 Meta-analysis Figures Figure 1 Figure 2 Figure 3 Introduction Lung cancer is the leading cause of cancer related deaths worldwide, which has posed a serious threat to the health and lives of people across the world 1 . According to histological subgroups, lung cancer is divided into two large categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC contributing to around 85% of all cases 2 . Despite recent advances in diagnostic and therapeutic procedures, including development of computed tomography–based screening to detect lung cancer early, molecular-targeted therapy and immunotherapy in the advanced lung cancer treatment, The prognosis of lung cancer patients remains poor, with a 5-year overall survival rate of 16% 3–5 . Research efforts have focused on identifying new biomarkers and molecular pathways that influence NSCLC progression. The recent discovery of CRABP2 and the exploration of the associated mechanisms have resulted in great advances in the area of lung cancer 6 7 . Studies have shown plasma CRABP2 levels might be a novel and promising prognostic marker in NSCLC. Retinoic acid (RA) is the most active metabolite of vitamin A and could influence the proliferation, differentiation, and apoptosis of normal and tumor cells 8 9 . A particular carrier for RA is cellular retinoic acid-binding protein 2 (CRABP2), a small cytosolic protein from the family of intracellular lipid-binding proteins 10 . By transiting RA to the nucleus and interacting with the nuclear retinoic acid receptor (RAR), CRABP2 activates RA’s transcriptional regulatory function and has the biological effects of controlling cell proliferation, death, and metastasis 11 12 13 . Some studies revealed aberrant CRABP expression in human cancers, which can be associated with clinicopathological characteristics and clinical prognosis. Thus, the decrease of CRABP2 expression was significantly associated with the presence of distant lymph node metastases in esophageal squamous cell carcinoma 14 . In addition, hypermethylation of CRABP2 promoter had an unfavorable prognostic value for hepatocellular carcinoma patients 11 . Conversely, Studies have reported that the absence of CRABP2 protein was associated with poor prognosis for head and neck squamous cell carcinoma patients 15 . On the other hand, the increase of CRABP2 expression was observed in later stages of human breast cancer 16 . Furthermore, in non-small cell lung cancer, kidney cancer, and glioma, elevated expression of CRABP2 was substantially related to a poor tumor prognosis 6 17 18 . These results indicate that CRABP2 may be involved in tumor growth and have controversial functions in various tumor types. The prognostic value of CRABP2 in lung cancer patients is still unknown. As a result, we intend to conduct a meta-analysis to comprehensively and systematically understand the prognostic value of CRABP2 in lung cancer patients. This study investigated the prognostic role of CRABP2 in lung cancer from the perspective of 2 survival indicators: OS and PFS. OS refers to the time from the beginning of the study until to death (due to any reason). PFS refers to the time from the beginning of the study until to the progression of the disease (due to any reason). Currently, only a few studies are available on the role of CRABP2 in lung cancer. The findings from these studies were taken into consideration in order to outline the criteria for exploration and explanation of the connection between CRABP2 and its prognostic value in lung cancer patients. The present study was conducted to assess the prognostic value of CRABP2 in lung cancer. Material and methods Search strategy The following databases were searched for the retrieval of relevant data: Cochrane Library, Embase, PubMed, and the Web of Science. The latest update of the search was May 1, 2023. The key terms used in the searches included “CRABP2” (e.g., “cellular retinoic acid-binding protein 2 ”); “Cellular Retinoic Acid-binding Protein 2 ” (e.g., “Crabp2”); and “lung cancer”[e.g., “lung neoplasm”, “lung carcinoma”,“non-small cell lung cancer (NSCLC)”,“small cell lung cancer (SCLC)”]. Inclusion and exclusion criteria Inclusion criteria for selecting the studies for this meta analysis were as follows criteria: ( 1 ) studied patients with lung cancer were pathological examination confirmed; ( 2 )the connection of CRABP2 with OS and/or progression-free survival (PFS) was reported. The exclusion criteria included letters, abstracts, reviews, case reports or basic studies; research reports of studies in languages other than Chinese and English; studies lacking data on assessing hazard ratio (HR),and 95% confidence interval (CI); and studies had duplicated data or analysis. Data extraction and quality assessment Two investigators (Guang Yang and Wenhao Wang) were involved in collecting the data. They independently procured the data from the available studies. In case where the retrieved studies could not be classified by title and abstract, the full text was reviewed. If disagreement appeared, two investigators discussed and reached consensus with a third investigator (Siwei Xu). During the data review process, details with respect to the following points were recorded: first author; year of publication; nationality; type of cancer; plasma level of CRABP2 expression; sample size; outcome indicators; HRs with 95% CIs. The Newcastle-Ottawa Scale (NOS) was used to assess each of the included studies quality by two independent authors (Guang Yang and Wenhao Wang). The NOS consists of three parts: selection(0–4 points), comparability (0–2 points), and outcome assessment (0–3 points).The studies with NOS scores of ≥ 6 were regarded as high-quality studies and eventually were enrolled into our meta-analysis. Statistical Analysis All statistical analyses were conducted using Review Manager 5.3(The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and STATA 12.0 software (STATA, College Station, TX). We directly obtained HR and 95%CI from each literature or estimated these data, HR > 1 indicated a worse prognosis in lung cancer patients with the elevated plasma level of CRABP2. Cochran’s Q test and Higgins I-squared statistic were undertaken to assess the heterogeneity of the included trials. Both fixed-effects (Mantel-Haenszel method) and random effects (DerSimonian - Laird method) models were used to calculate the pooled HRs and 95%CIs. A Pheterogeneity 2 > 50% suggested significant heterogeneity in the literature and a random-effect model was used. Otherwise, the fixed-effects model was adopted. Publication bias was assessed by Begg’s funnel plot and Egger’s linear regression test.All P - values were two-sided. The P < 0.05 was considered statistical significant. Results Identification of relevant studies A total of 14 studies published between 2013 and 2022 were initially collected. After carefully inspection of these available articles, 10 articles were eliminated and 4 studies were finally enrolled in our meta-analysis. The specific process of research selection was shown in the flow diagram (Fig. 1 ). Among them, Two studies were from China, one study was performed in Chinese TaiWan and Korea, respectively. HRs and 95%CIs were extracted directly in 4 studies, all of which calculated HRs by multivariate analysis. In our meta analysis, 4 studies illuminated the association between plasma level of CRABP2 and OS. 2 studies reported the association between plasma level of CRABP2 and PFS. The characteristics of the enrolled studies were shown in Table 1: Table.1: The basic characteristics of enrolled studies. First author Year Region Indicator Outcome(HR and 95%CI) NOS Do Jun Kim 2018 Korea OS 1.01(1.00-1.02) 7 Yong Zhang 2015 China OS 1.3(0.98–1.73) 8 Shuangshuang Zeng 2023 China OS 1.2(1.04–1.38) 8 PFS 0.84(0.64–1.09) Jun-I Wu 2018 Chinese TaiWan OS 1.2(1.04–1.39) 7 PFS 1.55(1.26–1.9) The plasma level of CRABP2 and OS in lung cancer Four studies reported the association between the elevated plasma level of CRABP2 and OS in lung cancer. For the purpose of analyzing the indicator of OS, 4 studies were selected. Since the obvious heterogeneity was observed in the studies (I 2 = 78.6%, P = 0.003), random effects model was adopted. The obtained results suggested that increased plasma level of CRABP2 predicted poor OS in lung cancer patient with a combined HR of 1.14 (95% CI: 1.00–1.30; Fig. 2 ). The plasma level of CRABP2 and PFS in lung cancer Two studies illustrated the association between the elevated plasma level of CRABP2 and PFS in lung cancer. Since the obvious heterogeneity was observed in the studies (I 2 = 92.2%, P = 0.0001), random effects model was adopted. Meta-analysis of these two studies revealed that patients with the increased plasma level of CRABP2 were not associated with poor PFS with combined HR:1.15% CI: 0.63–2.09, Fig. 3 ) in lung cancer. Publication Bias Publication bias was assessed by Begg’s funnel plot and Egger’s linear regression test, No publication bias was detected for OS and PFS in Begg test (Pr > jzj = 0.764) and Egger’s test (P > jt j = 0.328). Discussion Our meta-analysis included 4 studies, indicating that the elevated plasma level of CRABP2 significantly predicted poor OS (HR: 1.14 (95% CI: 1.00–1.30, Fig. 1 ) in lung cancer patients. There were 2 studies showing the data of association between the CRABP2 and PFS in lung cancer patients. The pooled HR of 1.15(95% CI: 0.63–2.09, Fig. 2 ) showed that patients with the increased plasma level of CRABP2 were not associated with poor PFS in lung cancer. Taking all these into consideration, The presence of elevated CRABP2 expression in lung cancer patients may be have a significant risk factor for poor prognostic factor for overall survival. Lung cancer causes more than one-fourth of all cancer-related deaths worldwide 3 . Nearly sixty percent of lung cancer patients are diagnosed at late stages with metastasis, and their 5-year survival is less than 16% 19 . Thus, identifications of novel therapeutic targets against lung cancer are urgently demanded to improve patients’ survival. Cellular retinoic acid-binding proteins, Crabp1 and Crabp2, are small cytosolic proteins that belong to a family of two isotypes 10 . CRABP2 is a cytosol-to-nuclear shuttling protein, which facilitates RA binding to its cognate receptor complex and transfer to the nucleus. CRABP2 encodes a member of the retinoic acid, which binds protein family and lipocalin/ cytosolic fatty-acid binding protein family 20 . CRABP2 was found to be upregulated in thyroid carcinoma and promoted the invasion, migration in thyroid cancer cells 21 . Downregulation of CRABP2 inhibits proliferation and metastasis and promotes cell apoptosis of hepatocellular carcinoma 11 . The overexpression of CRABP2 has been reported in tumor tissues of non-small cell lung cancer (NSCLC) 12,22,23 . However, the role of CRABP2 in lung cancer is still unclear. Studies have shown that expression of E-cadherin increased in the empty vector group compared to the CRABP2 overexpression group. Expression of MMP9 and vimentin in the CRABP2 overexpression group was higher than that in the empty vector group and siRNA transfection group. Inhibition of CRABP2 expression could reduce cell EMT. This indicates that overexpression of CRABP2 facilitates cellular proliferation and migration, whereas CRABP2 down-regulation reduces cellular proliferation and expression of EMT-related proteins. This suggests that reducing expression of the CRABP2 gene will benefit the survival rate in patients with NSCLC 23 . Recently proposed was an antitumorigenic mechanism of CRABP2 that is independent of retinoic acid 24 . CRABP2 enhances retinoic acid signaling, which is generally considered to be an antitumor activity. However, contradictory reports exist regarding the exact role of CRABP2 in general tumorigenesis; thus, further investigation is needed 25 . Recent proteomic analyses determined that high levels of CRABP2 are an adverse prognostic marker in estrogen receptor–negative breast tumors, and another study identified CRABP2 to be a subtype-specific biomarker for ovarian cancer 26 . Expression in serous ovarian cancer specimens was up-regulated, and CRABP2 expression was positively correlated with tumor grade and cancer stage. Elevated CRABP2 mRNA transcript levels were observed in retinoblastoma tissue compared with normal retinal tissue, and infiltrating retinoblastoma showed elevated levels of CRABP2 27 . Based on our results, this meta-analysis shown that the elevated CRABP2 expression significantly predicted poor OS in patients suffering from lung cancer. The plasma level of CRABP2 was not associated with PFS in patients with lung cancer. In conclusion, plasma CRABP2 can be used as a diagnostic and prognostic marker for NSCLC to reduce cancer cell proliferation, migration, and invasion by targeting inhibition. Nevertheless, the meta-analysis has also posed some limitations that need to be mentioned. First, the study was retrospective in nature, which could easily lead to some bias. Second, our meta-analysis only enrolled studies published in English language. So, it was more likely to appear publication bias. Third, only a limited number of documents were selected for the purpose of analysis. Further large-scale studies and randomized controlled trials need to be conducted in the future. In conclusion Our meta-analysis found the increased plasma level of CRABP2 was associated with poor OS independently in NSCLC patients. The plasma CRABP2 level may be an indicator of biological aggressiveness of the tumor. Our research was promising regarding the feasibility and utility of plasma CRABP2 as a novel prognostic biomarker in NSCLC, and the findings warrant further investigation. Abbreviations CI = confidence interval, PFS = Progression-free survival, HR = hazard ratio, OS = overall survival, CRABP2=cellular retinoic acid-binding protein 2, NSCLC= non-small cell lung cancer, SCLC= small cell lung cancer, NOS=Newcastle-Ottawa Scale, RA=Retinoic acid, RAR= Retinoic acid receptor. Declarations Acknowledgments I would like to thank professor Liu,for his guidance of this research and my colleagues for their strong support of this study. Authors’ contributions Huining Liu and Qifan Yin conceived the study. Guang Yang and Wenhao Wang collected the data and analyzed the data and performed statistical analyses. Siwei Xu searched researches. Qifan Yin drafted the manuscript. Huining Liu gave important intellectual contribution and critically revised the manuscript. All authors read and approved the final manuscript. Funding No funding was involved in this study. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study conforms to the ethical guidelines in a priori approval by the local Ethical Committee of The First Hospital of Hebei Medical University. This study was approved by our institutional review board (IRB number 20230605). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details 1 , Department of Thoracic Surgery, The First Hospital of Hebei Medical University, No. 89 Donggang Street, Yuhua District, 050031, Shijiazhuang, Hebei Province, People’s Republic of China. 2 , Department of Thoracic Surgery, Hebei Provincal General Hospital, No.348,West He-Ping Road, XinHua District, 050051,Shijiazhuang, Hebei Province, People’s Republic of China. References Cao M, Chen W. Epidemiology of lung cancer in China. Thorac cancer. 2019;10:3–7. Jenkins R, Walker J, Roy UB. 2022 cancer statistics: Focus on lung cancer. Future Oncology 2023;null:null. Siegel RL, Miller KD, Wagle NS, Jemal A, Cancer. statistics, 2023. Ca-a cancer journal for clinicians 2023;73:17–48. Wiener RS, Gould MK, Arenberg DA, et al. An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice. Am J Respir Crit Care Med. 2015;192:881–91. Ni M, Shi XL, Qu ZG, Jiang H, Chen ZQ, Hu J. Epithelial mesenchymal transition of non-small-cell lung cancer cells A549 induced by SPHK1. Asian Pac J Trop Med. 2015;8:142–6. Kim DJ, Kim WJ, Lim M, et al. Plasma CRABP2 as a Novel Biomarker in Patients with Non-Small Cell Lung Cancer. J Korean Med Sci. 2018;33:e178. Wu JI, Lin YP, Tseng CW, Chen HJ, Wang LH. Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling. Sci Rep. 2019;9:845. Ni X, Hu G, Cai X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit Rev Food Sci Nutr. 2019;59:71–s80. Arellano-Ortiz AL, Salcedo-Vargas M, Vargas-Requena CL, et al. DNA Methylation of Cellular Retinoic Acid-Binding Proteins in Cervical Cancer. Genet epigenetics. 2016;8:53–7. Honecker F, Rohlfing T, Harder S, et al. Proteome analysis of the effects of all-trans retinoic acid on human germ cell tumor cell lines. J Proteom. 2014;96:300–13. Chen Q, Tan L, Jin Z, Liu Y, Zhang Z. Downregulation of CRABP2 Inhibit the Tumorigenesis of Hepatocellular Carcinoma In Vivo and In Vitro. Biomed Res Int. 2020;2020:3098327. Han SS, Kim WJ, Hong Y, et al. RNA sequencing identifies novel markers of non-small cell lung cancer. Lung Cancer. 2014;84:229–35. Yi Q, Miao Y, Kong Y, et al. MiR-579 Inhibits Lung Adenocarcinoma Cell Proliferation and Metastasis via Binding to CRABP2. Comput Math Methods Med. 2022;2022:9111681. Yang Q, Wang R, Xiao W, Sun F, Yuan H, Pan Q. Cellular Retinoic Acid Binding Protein 2 Is Strikingly Downregulated in Human Esophageal Squamous Cell Carcinoma and Functions as a Tumor Suppressor. PLoS ONE. 2016;11:e0148381. Calmon MF, Rodrigues RV, Kaneto CM, et al. Epigenetic silencing of CRABP2 and MX1 in head and neck tumors. Neoplasia (New York NY). 2009;11:1329–39. Geiger T, Madden SF, Gallagher WM, Cox J, Mann M. Proteomic portrait of human breast cancer progression identifies novel prognostic markers. Cancer res. 2012;72:2428–39. Campos B, Centner FS, Bermejo JL, et al. Aberrant expression of retinoic acid signaling molecules influences patient survival in astrocytic gliomas. Am J Pathol. 2011;178:1953–64. Percicote AP, Mardegan GL, Gugelmim ES, et al. Tissue expression of retinoic acid receptor alpha and CRABP2 in metastatic nephroblastomas. Diagn Pathol. 2018;13:9. He J, Yu L, Wang CM, Zhou XF. MiR-1275 promotes non-small cell lung cancer cell proliferation and metastasis by regulating LZTS3 expression. Eur Rev Med Pharmacol Sci. 2022;26:2215. Meng JF, Luo MJ. CRABP2 involvement in a mechanism of Golgi stress and tumor dry matter in non-small cell lung cancer cells via ER dependent Hippo pathway. Acta Biochim Pol. 2021;69:31–6. Liu CL, Hsu YC, Kuo CY, Jhuang JY, Li YS, Cheng SP. CRABP2 Is Associated With Thyroid Cancer Recurrence and Promotes Invasion via the Integrin/FAK/AKT Pathway. Endocrinology 2022;163:null. Zhang Y, Wang H, Wang J, et al. Global analysis of chromosome 1 genes among patients with lung adenocarcinoma, squamous carcinoma, large-cell carcinoma, small-cell carcinoma, or non-cancer. Cancer Metastasis Rev. 2015;34:249–64. Codreanu SG, Hoeksema MD, Slebos RJC, et al. Identification of Proteomic Features To Distinguish Benign Pulmonary Nodules from Lung Adenocarcinoma. J Proteome Res. 2017;16:3266–76. Li G, Cai Y, Wang C, Huang M, Chen J. LncRNA GAS5 regulates the proliferation, migration, invasion and apoptosis of brain glioma cells through targeting GSTM3 expression. The effect of LncRNA GAS5 on glioma cells. J Neurooncol. 2019;143:525–36. Hui L, Zhang S, Wudu M, et al. CBLL1 is highly expressed in non-small cell lung cancer and promotes cell proliferation and invasion. Thorac cancer. 2019;10:1479–88. Wang D, Liu Y, Zhao W, Wang R, Tong X, Jiang G. [SRC kinase inhibitor PP2 inhibits invasion and metastasis of lung cancer A549 cells by upregulating connexin43 expression]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University. 2019;39:797–803. Ye L, Liu R, Lin P, Wang W. Krüppel-like transcription factor 16 transcriptional up-regulation of cellular retinoic acid-binding proteins-2 promotes the invasion and migration and inhibits apoptosis of retinoblastoma cells by regulating integrin-β1/focal adhesion kinase /extracellular signal-regulated kinase pathway. Bioengineered. 2022;13:3694–706. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 13 Jan, 2024 Reviews received at journal 07 Jan, 2024 Reviewers agreed at journal 07 Jan, 2024 Reviewers invited by journal 31 Jul, 2023 Submission checks completed at journal 28 Jun, 2023 Editor assigned by journal 28 Jun, 2023 First submitted to journal 20 Jun, 2023 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3088146","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":213864290,"identity":"d720ffd3-c883-4cbf-957c-15631999cafa","order_by":0,"name":"Guang Yang","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guang","middleName":"","lastName":"Yang","suffix":""},{"id":213864291,"identity":"98dfcb0e-2065-498b-adb9-85ad1c5293fe","order_by":1,"name":"Qifan Yin","email":"","orcid":"","institution":"Hebei Provincal General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qifan","middleName":"","lastName":"Yin","suffix":""},{"id":213864292,"identity":"799c0b4c-f924-4e9b-ae0a-a87cae428039","order_by":2,"name":"Wenhao Wang","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wenhao","middleName":"","lastName":"Wang","suffix":""},{"id":213864293,"identity":"8d75eeaa-3d64-43fe-8fd4-19da2d5450ac","order_by":3,"name":"Siwei Xu","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Siwei","middleName":"","lastName":"Xu","suffix":""},{"id":213864294,"identity":"e0870eeb-76fa-4baf-89b9-fe22fd56d4ef","order_by":4,"name":"Huining Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIie3PMWsCMRTA8RcCcXk2a4J+iAeCpyD1qwQKTh06ScdcA/cZTnDxSzjnuKFL6a2CXeSgUwfdRUoPilvMWGh+ZMjw/rwEIEn+oDsOAoAAAVjenp9nKKUNJ+KacEf4thjq0t9IutPpFapf1DOy5kbSw3GLTx/DTG4KpUSDBJ4dT4+hh2E2QvrEaXlwE8I9ZtxyvdoGk/EAqUbaVfnOqD1OrRe8H5lY5ekdyZvYpMlftDU+JhFLve62MDcC/4C6rFzwL1LWW/V1rufUvB5adrmfS+mq4ymQXCnze2M2Zv5nn48cTJIk+Xe+AZQfSh190aeZAAAAAElFTkSuQmCC","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Huining","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2023-06-20 15:29:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3088146/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3088146/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":39390909,"identity":"d966517f-3c29-4855-ab5d-b44feeba2ffb","added_by":"auto","created_at":"2023-06-30 20:47:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12831,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow diagram\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3088146/v1/6d9baed6d8054f659ecb02c6.png"},{"id":39390907,"identity":"dccd7027-2e32-466f-aabf-450848bca5e7","added_by":"auto","created_at":"2023-06-30 20:47:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11333,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis of the relation between the plasma level of CRABP2 and OS in lung cancer.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3088146/v1/b077c09e50c2643dfce0535f.png"},{"id":39390908,"identity":"cbced226-62f7-4cb2-8bce-5a2a614a992b","added_by":"auto","created_at":"2023-06-30 20:47:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":9476,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis of the association between the plasma level of CRABP2 and PFS in lung cancer.\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3088146/v1/3e35e63538f6b9e780bd1e57.png"},{"id":39390910,"identity":"23e7eadb-29f7-4708-90d5-9847ef4276f3","added_by":"auto","created_at":"2023-06-30 20:47:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":331604,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3088146/v1/1b121136-c7bc-4a9e-b61e-140f4029fbad.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic role of CRABP2 in lung cancer：A meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer is the leading cause of cancer related deaths worldwide, which has posed a serious threat to the health and lives of people across the world \u003csup\u003e1\u003c/sup\u003e. According to histological subgroups, lung cancer is divided into two large categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC contributing to around 85% of all cases \u003csup\u003e2\u003c/sup\u003e. Despite recent advances in diagnostic and therapeutic procedures, including development of computed tomography\u0026ndash;based screening to detect lung cancer early, molecular-targeted therapy and immunotherapy in the advanced lung cancer treatment, The prognosis of lung cancer patients remains poor, with a 5-year overall survival rate of 16% \u003csup\u003e3\u0026ndash;5\u003c/sup\u003e. Research efforts have focused on identifying new biomarkers and molecular pathways that influence NSCLC progression. The recent discovery of CRABP2 and the exploration of the associated mechanisms have resulted in great advances in the area of lung cancer \u003csup\u003e6 7\u003c/sup\u003e. Studies have shown plasma CRABP2 levels might be a novel and promising prognostic marker in NSCLC.\u003c/p\u003e \u003cp\u003eRetinoic acid (RA) is the most active metabolite of vitamin A and could influence the proliferation, differentiation, and apoptosis of normal and tumor cells \u003csup\u003e8 9\u003c/sup\u003e. A particular carrier for RA is cellular retinoic acid-binding protein 2 (CRABP2), a small cytosolic protein from the family of intracellular lipid-binding proteins \u003csup\u003e10\u003c/sup\u003e. By transiting RA to the nucleus and interacting with the nuclear retinoic acid receptor (RAR), CRABP2 activates RA\u0026rsquo;s transcriptional regulatory function and has the biological effects of controlling cell proliferation, death, and metastasis \u003csup\u003e11 12 13\u003c/sup\u003e. Some studies revealed aberrant CRABP expression in human cancers, which can be associated with clinicopathological characteristics and clinical prognosis. Thus, the decrease of CRABP2 expression was significantly associated with the presence of distant lymph node metastases in esophageal squamous cell carcinoma \u003csup\u003e14\u003c/sup\u003e. In addition, hypermethylation of CRABP2 promoter had an unfavorable prognostic value for hepatocellular carcinoma patients\u003csup\u003e11\u003c/sup\u003e. Conversely, Studies have reported that the absence of CRABP2 protein was associated with poor prognosis for head and neck squamous cell carcinoma patients \u003csup\u003e15\u003c/sup\u003e. On the other hand, the increase of CRABP2 expression was observed in later stages of human breast cancer \u003csup\u003e16\u003c/sup\u003e. Furthermore, in non-small cell lung cancer, kidney cancer, and glioma, elevated expression of CRABP2 was substantially related to a poor tumor prognosis \u003csup\u003e6 17 18\u003c/sup\u003e. These results indicate that CRABP2 may be involved in tumor growth and have controversial functions in various tumor types. The prognostic value of CRABP2 in lung cancer patients is still unknown. As a result, we intend to conduct a meta-analysis to comprehensively and systematically understand the prognostic value of CRABP2 in lung cancer patients.\u003c/p\u003e \u003cp\u003eThis study investigated the prognostic role of CRABP2 in lung cancer from the perspective of 2 survival indicators: OS and PFS. OS refers to the time from the beginning of the study until to death (due to any reason). PFS refers to the time from the beginning of the study until to the progression of the disease (due to any reason). Currently, only a few studies are available on the role of CRABP2 in lung cancer. The findings from these studies were taken into consideration in order to outline the criteria for exploration and explanation of the connection between CRABP2 and its prognostic value in lung cancer patients. The present study was conducted to assess the prognostic value of CRABP2 in lung cancer.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eThe following databases were searched for the retrieval of relevant data: Cochrane Library, Embase, PubMed, and the Web of Science. The latest update of the search was May 1, 2023. The key terms used in the searches included \u0026ldquo;CRABP2\u0026rdquo; (e.g., \u0026ldquo;cellular retinoic acid-binding protein 2 \u0026rdquo;); \u0026ldquo;Cellular Retinoic Acid-binding Protein 2 \u0026rdquo; (e.g., \u0026ldquo;Crabp2\u0026rdquo;); and \u0026ldquo;lung cancer\u0026rdquo;[e.g., \u0026ldquo;lung neoplasm\u0026rdquo;, \u0026ldquo;lung carcinoma\u0026rdquo;,\u0026ldquo;non-small cell lung cancer (NSCLC)\u0026rdquo;,\u0026ldquo;small cell lung cancer (SCLC)\u0026rdquo;].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eInclusion criteria for selecting the studies for this meta analysis were as follows criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) studied patients with lung cancer were pathological examination confirmed; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)the connection of CRABP2 with OS and/or progression-free survival (PFS) was reported. The exclusion criteria included letters, abstracts, reviews, case reports or basic studies; research reports of studies in languages other than Chinese and English; studies lacking data on assessing hazard ratio (HR),and 95% confidence interval (CI); and studies had duplicated data or analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData extraction and quality assessment\u003c/h2\u003e \u003cp\u003eTwo investigators (Guang Yang and Wenhao Wang) were involved in collecting the data. They independently procured the data from the available studies. In case where the retrieved studies could not be classified by title and abstract, the full text was reviewed. If disagreement appeared, two investigators discussed and reached consensus with a third investigator (Siwei Xu). During the data review process, details with respect to the following points were recorded: first author; year of publication; nationality; type of cancer; plasma level of CRABP2 expression; sample size; outcome indicators; HRs with 95% CIs. The Newcastle-Ottawa Scale (NOS) was used to assess each of the included studies quality by two independent authors (Guang Yang and Wenhao Wang). The NOS consists of three parts: selection(0\u0026ndash;4 points), comparability (0\u0026ndash;2 points), and outcome assessment (0\u0026ndash;3 points).The studies with NOS scores of \u0026ge;\u0026thinsp;6 were regarded as high-quality studies and eventually were enrolled into our meta-analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003e All statistical analyses were conducted using Review Manager 5.3(The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and STATA 12.0 software (STATA, College Station, TX). We directly obtained HR and 95%CI from each literature or estimated these data, HR\u0026thinsp;\u0026gt;\u0026thinsp;1 indicated a worse prognosis in lung cancer patients with the elevated plasma level of CRABP2. Cochran\u0026rsquo;s Q test and Higgins I-squared statistic were undertaken to assess the heterogeneity of the included trials. Both fixed-effects (Mantel-Haenszel method) and random effects (DerSimonian - Laird method) models were used to calculate the pooled HRs and 95%CIs. A Pheterogeneity\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% suggested significant heterogeneity in the literature and a random-effect model was used. Otherwise, the fixed-effects model was adopted. Publication bias was assessed by Begg\u0026rsquo;s funnel plot and Egger\u0026rsquo;s linear regression test.All \u003cem\u003eP\u003c/em\u003e- values were two-sided. The \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistical significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eIdentification of relevant studies\u003c/h2\u003e \u003cp\u003eA total of 14 studies published between 2013 and 2022 were initially collected. After carefully inspection of these available articles, 10 articles were eliminated and 4 studies were finally enrolled in our meta-analysis. The specific process of research selection was shown in the flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among them, Two studies were from China, one study was performed in Chinese TaiWan and Korea, respectively. HRs and 95%CIs were extracted directly in 4 studies, all of which calculated HRs by multivariate analysis. In our meta analysis, 4 studies illuminated the association between plasma level of CRABP2 and OS. 2 studies reported the association between plasma level of CRABP2 and PFS. The characteristics of the enrolled studies were shown in Table\u0026nbsp;1:\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable.1: The basic characteristics of enrolled studies.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst author\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndicator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOutcome(HR and 95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDo Jun Kim\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.01(1.00-1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYong Zhang\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.3(0.98\u0026ndash;1.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShuangshuang Zeng\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.2(1.04\u0026ndash;1.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.84(0.64\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJun-I Wu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChinese TaiWan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.2(1.04\u0026ndash;1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.55(1.26\u0026ndash;1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eThe plasma level of CRABP2 and OS in lung cancer\u003c/h2\u003e \u003cp\u003eFour studies reported the association between the elevated plasma level of CRABP2 and OS in lung cancer. For the purpose of analyzing the indicator of OS, 4 studies were selected. Since the obvious heterogeneity was observed in the studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;78.6%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), random effects model was adopted. The obtained results suggested that increased plasma level of CRABP2 predicted poor OS in lung cancer patient with a combined HR of 1.14 (95% CI: 1.00\u0026ndash;1.30; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eThe plasma level of CRABP2 and PFS in lung cancer\u003c/h2\u003e \u003cp\u003eTwo studies illustrated the association between the elevated plasma level of CRABP2 and PFS in lung cancer. Since the obvious heterogeneity was observed in the studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;92.2%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0001), random effects model was adopted. Meta-analysis of these two studies revealed that patients with the increased plasma level of CRABP2 were not associated with poor PFS with combined HR:1.15% CI: 0.63\u0026ndash;2.09, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) in lung cancer.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePublication Bias\u003c/h2\u003e \u003cp\u003ePublication bias was assessed by Begg\u0026rsquo;s funnel plot and Egger\u0026rsquo;s linear regression test, No publication bias was detected for OS and PFS in Begg test (Pr\u0026thinsp;\u0026gt;\u0026thinsp;jzj\u0026thinsp;=\u0026thinsp;0.764) and Egger\u0026rsquo;s test (P\u0026thinsp;\u0026gt;\u0026thinsp;jt j\u0026thinsp;=\u0026thinsp;0.328).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur meta-analysis included 4 studies, indicating that the elevated plasma level of CRABP2 significantly predicted poor OS (HR: 1.14 (95% CI: 1.00\u0026ndash;1.30, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) in lung cancer patients. There were 2 studies showing the data of association between the CRABP2 and PFS in lung cancer patients. The pooled HR of 1.15(95% CI: 0.63\u0026ndash;2.09, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) showed that patients with the increased plasma level of CRABP2 were not associated with poor PFS in lung cancer. Taking all these into consideration, The presence of elevated CRABP2 expression in lung cancer patients may be have a significant risk factor for poor prognostic factor for overall survival.\u003c/p\u003e \u003cp\u003eLung cancer causes more than one-fourth of all cancer-related deaths worldwide\u003csup\u003e3\u003c/sup\u003e. Nearly sixty percent of lung cancer patients are diagnosed at late stages with metastasis, and their 5-year survival is less than 16%\u003csup\u003e19\u003c/sup\u003e. Thus, identifications of novel therapeutic targets against lung cancer are urgently demanded to improve patients\u0026rsquo; survival. Cellular retinoic acid-binding proteins, Crabp1 and Crabp2, are small cytosolic proteins that belong to a family of two isotypes\u003csup\u003e10\u003c/sup\u003e. CRABP2 is a cytosol-to-nuclear shuttling protein, which facilitates RA binding to its cognate receptor complex and transfer to the nucleus. CRABP2 encodes a member of the retinoic acid, which binds protein family and lipocalin/ cytosolic fatty-acid binding protein family\u003csup\u003e20\u003c/sup\u003e. CRABP2 was found to be upregulated in thyroid carcinoma and promoted the invasion, migration in thyroid cancer cells \u003csup\u003e21\u003c/sup\u003e. Downregulation of CRABP2 inhibits proliferation and metastasis and promotes cell apoptosis of hepatocellular carcinoma\u003csup\u003e11\u003c/sup\u003e. The overexpression of CRABP2 has been reported in tumor tissues of non-small cell lung cancer (NSCLC) \u003csup\u003e12,22,23\u003c/sup\u003e. However, the role of CRABP2 in lung cancer is still unclear.\u003c/p\u003e \u003cp\u003eStudies have shown that expression of E-cadherin increased in the empty vector group compared to the CRABP2 overexpression group. Expression of MMP9 and vimentin in the CRABP2 overexpression group was higher than that in the empty vector group and siRNA transfection group. Inhibition of CRABP2 expression could reduce cell EMT. This indicates that overexpression of CRABP2 facilitates cellular proliferation and migration, whereas CRABP2 down-regulation reduces cellular proliferation and expression of EMT-related proteins. This suggests that reducing expression of the CRABP2 gene will benefit the survival rate in patients with NSCLC\u003csup\u003e23\u003c/sup\u003e. Recently proposed was an antitumorigenic mechanism of CRABP2 that is independent of retinoic acid\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCRABP2 enhances retinoic acid signaling, which is generally considered to be an antitumor activity. However, contradictory reports exist regarding the exact role of CRABP2 in general tumorigenesis; thus, further investigation is needed\u003csup\u003e25\u003c/sup\u003e. Recent proteomic analyses determined that high levels of CRABP2 are an adverse prognostic marker in estrogen receptor\u0026ndash;negative breast tumors, and another study identified CRABP2 to be a subtype-specific biomarker for ovarian cancer\u003csup\u003e26\u003c/sup\u003e. Expression in serous ovarian cancer specimens was up-regulated, and CRABP2 expression was positively correlated with tumor grade and cancer stage. Elevated CRABP2 mRNA transcript levels were observed in retinoblastoma tissue compared with normal retinal tissue, and infiltrating retinoblastoma showed elevated levels of CRABP2 \u003csup\u003e27\u003c/sup\u003e. Based on our results, this meta-analysis shown that the elevated CRABP2 expression significantly predicted poor OS in patients suffering from lung cancer. The plasma level of CRABP2 was not associated with PFS in patients with lung cancer. In conclusion, plasma CRABP2 can be used as a diagnostic and prognostic marker for NSCLC to reduce cancer cell proliferation, migration, and invasion by targeting inhibition.\u003c/p\u003e \u003cp\u003eNevertheless, the meta-analysis has also posed some limitations that need to be mentioned. First, the study was retrospective in nature, which could easily lead to some bias. Second, our meta-analysis only enrolled studies published in English language. So, it was more likely to appear publication bias. Third, only a limited number of documents were selected for the purpose of analysis. Further large-scale studies and randomized controlled trials need to be conducted in the future.\u003c/p\u003e \u003cp\u003eIn conclusion\u003c/p\u003e \u003cp\u003eOur meta-analysis found the increased plasma level of CRABP2 was associated with poor OS independently in NSCLC patients. The plasma CRABP2 level may be an indicator of biological aggressiveness of the tumor. Our research was promising regarding the feasibility and utility of plasma CRABP2 as a novel prognostic biomarker in NSCLC, and the findings warrant further investigation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI = confidence interval, PFS = Progression-free survival, HR = hazard ratio, OS = overall survival, CRABP2=cellular retinoic acid-binding protein 2, NSCLC= non-small cell lung cancer, SCLC= small cell lung cancer, NOS=Newcastle-Ottawa Scale, RA=Retinoic acid, RAR= Retinoic acid receptor.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI would like to thank professor Liu,for his guidance of this research and my colleagues for their strong support of this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuining Liu and Qifan Yin conceived the study. Guang Yang and Wenhao Wang collected the data and analyzed the data and performed statistical analyses. Siwei Xu searched researches. Qifan Yin drafted the manuscript. Huining Liu gave important intellectual contribution and critically revised the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was involved in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study conforms to the ethical guidelines in a priori approval by the local Ethical Committee of\u0026nbsp;The\u0026nbsp;First Hospital of Hebei Medical University. This study was approved by our institutional review board (IRB number 20230605).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e, Department of Thoracic Surgery,\u0026nbsp;The First Hospital of Hebei Medical University, No. 89 Donggang Street, Yuhua District, 050031,\u0026nbsp;Shijiazhuang, Hebei Province, People\u0026rsquo;s Republic of China.\u0026nbsp;\u003csup\u003e2\u003c/sup\u003e, Department of Thoracic Surgery, Hebei Provincal General Hospital,\u0026nbsp;No.348,West He-Ping Road,\u0026nbsp;XinHua District,\u0026nbsp;050051,Shijiazhuang, Hebei Province, People\u0026rsquo;s Republic of China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCao M, Chen W. Epidemiology of lung cancer in China. Thorac cancer. 2019;10:3\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJenkins R, Walker J, Roy UB. 2022 cancer statistics: Focus on lung cancer. Future Oncology 2023;null:null.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiegel RL, Miller KD, Wagle NS, Jemal A, Cancer. statistics, 2023. Ca-a cancer journal for clinicians 2023;73:17\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiener RS, Gould MK, Arenberg DA, et al. An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice. Am J Respir Crit Care Med. 2015;192:881\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNi M, Shi XL, Qu ZG, Jiang H, Chen ZQ, Hu J. Epithelial mesenchymal transition of non-small-cell lung cancer cells A549 induced by SPHK1. Asian Pac J Trop Med. 2015;8:142\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim DJ, Kim WJ, Lim M, et al. Plasma CRABP2 as a Novel Biomarker in Patients with Non-Small Cell Lung Cancer. J Korean Med Sci. 2018;33:e178.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu JI, Lin YP, Tseng CW, Chen HJ, Wang LH. Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling. Sci Rep. 2019;9:845.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNi X, Hu G, Cai X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit Rev Food Sci Nutr. 2019;59:71\u0026ndash;s80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArellano-Ortiz AL, Salcedo-Vargas M, Vargas-Requena CL, et al. DNA Methylation of Cellular Retinoic Acid-Binding Proteins in Cervical Cancer. Genet epigenetics. 2016;8:53\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHonecker F, Rohlfing T, Harder S, et al. Proteome analysis of the effects of all-trans retinoic acid on human germ cell tumor cell lines. J Proteom. 2014;96:300\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Q, Tan L, Jin Z, Liu Y, Zhang Z. Downregulation of CRABP2 Inhibit the Tumorigenesis of Hepatocellular Carcinoma In Vivo and In Vitro. Biomed Res Int. 2020;2020:3098327.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan SS, Kim WJ, Hong Y, et al. RNA sequencing identifies novel markers of non-small cell lung cancer. Lung Cancer. 2014;84:229\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYi Q, Miao Y, Kong Y, et al. MiR-579 Inhibits Lung Adenocarcinoma Cell Proliferation and Metastasis via Binding to CRABP2. Comput Math Methods Med. 2022;2022:9111681.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang Q, Wang R, Xiao W, Sun F, Yuan H, Pan Q. Cellular Retinoic Acid Binding Protein 2 Is Strikingly Downregulated in Human Esophageal Squamous Cell Carcinoma and Functions as a Tumor Suppressor. PLoS ONE. 2016;11:e0148381.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalmon MF, Rodrigues RV, Kaneto CM, et al. Epigenetic silencing of CRABP2 and MX1 in head and neck tumors. Neoplasia (New York NY). 2009;11:1329\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeiger T, Madden SF, Gallagher WM, Cox J, Mann M. Proteomic portrait of human breast cancer progression identifies novel prognostic markers. Cancer res. 2012;72:2428\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCampos B, Centner FS, Bermejo JL, et al. Aberrant expression of retinoic acid signaling molecules influences patient survival in astrocytic gliomas. Am J Pathol. 2011;178:1953\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePercicote AP, Mardegan GL, Gugelmim ES, et al. Tissue expression of retinoic acid receptor alpha and CRABP2 in metastatic nephroblastomas. Diagn Pathol. 2018;13:9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe J, Yu L, Wang CM, Zhou XF. MiR-1275 promotes non-small cell lung cancer cell proliferation and metastasis by regulating LZTS3 expression. Eur Rev Med Pharmacol Sci. 2022;26:2215.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeng JF, Luo MJ. CRABP2 involvement in a mechanism of Golgi stress and tumor dry matter in non-small cell lung cancer cells via ER dependent Hippo pathway. Acta Biochim Pol. 2021;69:31\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu CL, Hsu YC, Kuo CY, Jhuang JY, Li YS, Cheng SP. CRABP2 Is Associated With Thyroid Cancer Recurrence and Promotes Invasion via the Integrin/FAK/AKT Pathway. Endocrinology 2022;163:null.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Wang H, Wang J, et al. Global analysis of chromosome 1 genes among patients with lung adenocarcinoma, squamous carcinoma, large-cell carcinoma, small-cell carcinoma, or non-cancer. Cancer Metastasis Rev. 2015;34:249\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCodreanu SG, Hoeksema MD, Slebos RJC, et al. Identification of Proteomic Features To Distinguish Benign Pulmonary Nodules from Lung Adenocarcinoma. J Proteome Res. 2017;16:3266\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi G, Cai Y, Wang C, Huang M, Chen J. LncRNA GAS5 regulates the proliferation, migration, invasion and apoptosis of brain glioma cells through targeting GSTM3 expression. The effect of LncRNA GAS5 on glioma cells. J Neurooncol. 2019;143:525\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHui L, Zhang S, Wudu M, et al. CBLL1 is highly expressed in non-small cell lung cancer and promotes cell proliferation and invasion. Thorac cancer. 2019;10:1479\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang D, Liu Y, Zhao W, Wang R, Tong X, Jiang G. [SRC kinase inhibitor PP2 inhibits invasion and metastasis of lung cancer A549 cells by upregulating connexin43 expression]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University. 2019;39:797\u0026ndash;803.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe L, Liu R, Lin P, Wang W. Kr\u0026uuml;ppel-like transcription factor 16 transcriptional up-regulation of cellular retinoic acid-binding proteins-2 promotes the invasion and migration and inhibits apoptosis of retinoblastoma cells by regulating integrin-β1/focal adhesion kinase /extracellular signal-regulated kinase pathway. Bioengineered. 2022;13:3694\u0026ndash;706.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Lung cancer, Prognosis, CRABP2, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-3088146/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3088146/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe prognostic value of cellular retinoic acid-binding protein 2 (CRABP2), in lung cancer patients remains to be uncertained. Therefore, our research attempted to assess the relationship between CRABP2 and survival analysis in lung cancer patients through meta-analysis.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eRelated literature retrieved from Cochrane Library, Ovid, Embase, PubMed, the CNKI, and the Web of Science. The latest update of the search was May 1, 2023. The outcome indicators included as effective measures in the study were hazard ratio (HR), and 95% confidence interval (CI). The Stata 12.0 software was used to analyze the data.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 4 studies were finally enrolled in our meta-analysis. The increased plasma level of CRABP2 predicted poor OS in lung cancer patient with a combined HR of 1.14 (95% CI: 1.00\u0026ndash;1.30), and were not associated with poor PFS with combined HR:1.15% CI: 0.63\u0026ndash;2.09) in lung cancer patients.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur meta-analysis found the increased plasma level of CRABP2 was associated with poor OS independently in NSCLC patients. The plasma CRABP2 level may be an indicator of biological aggressiveness of the tumor. Our research was promising regarding the feasibility and utility of plasma CRABP2 as a novel prognostic biomarker in NSCLC, and the findings warrant further investigation.\u003c/p\u003e","manuscriptTitle":"Prognostic role of CRABP2 in lung cancer：A meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-06-30 20:46:58","doi":"10.21203/rs.3.rs-3088146/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-13T14:59:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-07T14:29:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8b939925-8335-42a5-84b8-0f832836c97e","date":"2024-01-07T13:21:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-08-01T03:54:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-06-28T05:11:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-06-28T05:11:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2023-06-20T15:25:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"db9976e5-ecce-4446-b29e-6e20050887b2","owner":[],"postedDate":"June 30th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-15T07:08:30+00:00","versionOfRecord":[],"versionCreatedAt":"2023-06-30 20:46:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3088146","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3088146","identity":"rs-3088146","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}