{"paper_id":"70960acd-1d8f-4f28-8dbf-b1041fee62bf","body_text":"Original Article | JOGCR. 2024; 9(6): 658-666 \n     Volume 9, November – December 2024       Journal of Obstetrics, Gynecology and Cancer Research \n Journal of Obstetrics, Gynecology and Cancer Research | ISSN: 2476-5848 \n \nClinicopathological Implications of Serum level of IL-27 in Endometrial \nCancer Patients \n \nFatemeh Sedaghat1 , Zahra Shiravani2 , Ali Mohammad Karimi1, Mohammad Reza Haghshenas1,  \nAbbas Ghaderi1, Mohammad Javad Fattahi1*  \n \n1. Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran \n2. Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, \nIran \n \nArticle Info  ABSTRACT \n  \n          10.30699/jogcr.9.6.658 \n \n \n \nBackground & Objective:  Endometrial cancer (EC) is the most prevalent \ngynecological malignancy in more developed countries. Multiple researches have been \ndone about the role of IL -27 in different cancers that suggest a dual role for this \ncytokine. In the present study, we evaluated the serum level of IL-27 in endometrial \ncancer patients. We also investigated the correlations between serum levels of IL-27 \nand the demographic and clinicopathologic features of the patients. \nMaterials & Methods: In this case-control study, 65 endometrial cancer patients and \n58 sex-age-match healthy controls were investigated. Serum levels of IL -27 in both \ncases and the control group were assessed by a reliable and specific sandwich enzyme-\nlinked immunosorbent assay (ELISA) kit and results were analyzed with SPSS. \nResults: We observed that the serum level of IL-27 in EC patients was dramatically \nhigher than in the control group (P=0.003). Additionally, Higher grades of EC (grade II \nand III) showed higher IL-27 serum levels compared to the control (P=0.006 and P=0.01 \nrespectively). No significant correlations between serum levels of IL -27 and lymph \nnode involvement, tumor stage, tumor size, and demographic features of the patients \nwere detected.  \nConclusion: Our results showed that there is a statistically significant difference \nbetween serum levels of IL-27 in EC patients and controls. Therefore, the serum level \nof IL-27 may exert a role in the pathogenesis of endometrial carcinoma, although \nfurther studies are needed. \nKeywords: Cytokines, Endometrial cancer, Gynecological Malignancy, IL -27 \nReceived:  2024/03/03; \nAccepted: 2024/07/14; \nPublished Online: 10 Oct 2024; \n \n \nUse your device to scan and read the \narticle online \n \n \nCorresponding Information:  \nMohammad Javad Fattahi, \nShiraz Institute for Cancer Research, School \nof Medicine, Shiraz University of Medical \nSciences, Shiraz, Iran \n \nEmail: mfattahi@sums.ac.ir \n \n \nCopyright © 2024, This is an original open-access article distributed under the terms of the Creative Commons Attribution-noncommercial 4.0 International License \nwhich permits copy and redistribution of the material just in noncommercial usages with proper citation. \n \n \nIntroduction\nEndometrial carcinoma (EC), a tumor originating in \nthe uterine epithelium, is the most prevalent \ngynecological malignancy in the United States and \nWestern countries (1). EC incidence rate is increasing, \nand multiple factors are involved, including increasing \nin life expectancies and obesity (2). EC can classify \ninto two different groups: type I which occurs in the \nyounger, pre -menopausal population is hormone -\ndependent and has a good prognosis while Type II is \nmore common in older, post -menopausal women and \nis considered estrogen -independent. Type II EC is \nusually more aggressive with a very poor prognosis (3, \n4). The main risk factors of EC are old age (over 55 \nyears), estrogens exposure (endogenous or exogenous), \nobesity, diabetes, early menarche; nulliparity, late -\nonset menopause, and tamoxifen use (5 -8). Although \nthe etiology of EC is not clear, it is now widely \nunderstood that genetic and environmental factors \ninteract to impact the risk of developing EC (9). \nInflammation can also contribute to EC progression \n(10). In the inflammatory process, cytokines play a \nsubstantial role as key mediators. The role of different \nkinds of cytokines including IL -27 is extensively \ninvestigated in different kinds of diseases and immune \nconditions. Several studies on the role of IL -27 in \nclinical disorders have shown that this cytokine can \ninfluence the pathogenesis of chronic diseases such as \ncoronary artery disease (11), Parkinson’s disease (12),  \nrheumatoid arthritis (RA) (13), tuberculosis (TB) (14), \nviral infections (15, 16), systemic lupus erythematosus \n(SLE) (17), as well as cancers (18, 19).  \nIL-27 is a new heterodimeric cytokine related to the \nIL-6/IL-12 family, which was identif ied in 2002 by \nPflanz et al (20).  Epstein -Barr Virus-induced gene 3 \nprotein (EBI3) and IL -27p28 (IL-27A) are subunits of \nIL-27. IL -27 binds to a heterodimeric receptor \n\n\n659 L-27 Serum Levels in Endometrial Cancer \n      Volume 9, November – December 2024       Journal of Obstetrics, Gynecology and Cancer Research \nconsisting of gp130 and IL -27 receptor alpha (IL -\n27Ra) also known as WSX1 and activates  the \nJAK/STAT signaling pathway (21 -23). iAntigen-\npresenting cells (APCs) such as macrophages (MQs) \nand dendritic cells (DCs) as well as epithelial cells are \nthe main producers of IL-27 (24). \nIL-27 has a complex effect and various research have \nrevealed that it has a dual role in innate and adaptive \nimmunity (25). This cytokine has been discovered to \nhave immune -enhancing properties via increasing T \ncell and natural killer (NK) cell proliferation as well as \nIFN- γ generation (20). However, by limiting T cel l \nresponses, IL-27 may act as a regulatory cytokine (26). \nIt has been also reported that the IL -27 can promote \nTreg development or conversion, induce IL -10 in T \nhelper cells (Th1, Th2, and Th17), and increase the \nexpression of PD-L1 on immune and nonimmune cells \n(27). The impact of IL -27 on cancers is controversial. \nIL-27 administration has been demonstrated to have \nsome effects on the immunological pathways that \ncontribute to tumor elimination, while sometimes IL -\n27 effects are in favor of tumorigenesis (27, 28).   \nIn this study, we aimed to examine the serum level \nof IL-27 in EC patients to determine its possible role in \nEC pathogenesis. In addition, the association between \nclinicopathologic and demographic factors of patients \nand serum level of IL-27 was evaluated. \n \nMethods \n2.1 Study population \nThe present study included 65 cases with clinical and \nhistopathological diagnosis of EC who had no previous \nhistory of additional neoplasms and autoimmune \ndiseases. According to pathological typing, all the \nselected EC patients had endometrioid \nadenocarcinoma. Sampling was done before any kind \nof treatment including chemo -radiation therapy, \nimmunotherapy, or surgery. They were recruited from \nthe gynecology clinic of Motahari and Faghihi hospital \naffiliated with Shiraz University of Medical Sciences \n(Shiraz, Iran). 58 age-matched healthy women without \nany evidence or history of genetic disorders, \nautoimmune diseases, cancer, and infectious diseases \nat least for the past four months were randomly selected \nfrom Shiraz Blood Transfusion Organization and \nconsidered as the control group. To determine the \ntumor stage and grade, we used the International \nFederation of Gynecology and Obstetrics (FIGO) \nclassification. \nThe research ethics committee of Shiraz University \nof Medical Sciences approved the study \n(IR.sums.med.rec.1399.91), and all participants \nprovided written informed permission before \nparticipating in the study. \n2.2 ELISA analysis \nThree millilitres of the peripheral blood was obtained \nfrom both case and control groups; the sera were \nseparated by centrifugati on and stored at - 70◦C until \nanalysis. Serum levels of IL-27 in all participants were \nmeasured by a specific sandwich ELISA kit (BT \nlaboratory, Shanghai, China) according to the \nmanufacturer’s procedures and using the standard \nconcentrations of IL -27, prov ided by BT laboratory, \nand presented as pg/ml. \n2.3 Statistical analysis \nFor data analysis, Statistical Package for Social \nSciences (SPSS, version 20.0; IBM Corporation, USA) \nwas used. The Kolmogorov- Smirnov and Shapiro -\nWilk tests were performed to assess t he normality of \ndata. Variables with normal distribution are presented \nas mean ± (SD), otherwise as median and first and third \ninterquartile ranges (IQR). Appropriate parametric (T -\ntest, Anova) and non -parametric ( Mann–Whitney U -\ntest, Kruskal –Wallis), Chi-square, and Fisher's exact \ntests were used for comparison between groups.  \nFurthermore, Spearman's Rho test was used to analyze \nthe possible effect of demographic features such as \nbody mass index, menarche age, and menopause age \non the serum level of IL -27 in patients. We also \ncalculated the area under the ROC curve (AUC) to \nevaluate the utility of IL-27 in distinguishing EC from \nnormal conditions, and the optimal cut-off value for IL-\n27, additionally its specificity and sensitivity were \nmeasured. In the present study, P values of 0.05 or less \nwere considered statistically significant. \n \nResults \nIn the present study, a total number of 65 EC patients \nand 58 age -matched healthy women as the control \ngroup were evaluated. The age range was between 30 \nand 86 years in EC patients, with a mean age of \n56.5±11.48. In the control group, the age range was \nbetween 26 and 74 years with a mean age of \n52.34±10.78. There was no significant difference in the \nmean age between EC patients and controls (p>0.05). \nRegarding tumor grades, 31 cases (47.7%) suffered \nfrom grade I, 20 cases (30.8%) from grade II, and 14 \ncases (21.5%) from grade III of the tumor.  The \nbaseline clinicopathologic features of patients and their \nassociations with serum levels of IL -27 are pre sented \nin Table 1. No statistically significant relationship was \nobserved between serum levels of IL -27 and patient’s \nage (P=0.14), tumor size (P=0.54), tumor stage \n(P=0.79) and lymph node involvement (P=0.47) (Table \n1). \nThe serum levels of IL-27 in patients and the control \ngroup were 265.80 (196.50- 346.60) pg/ml and 204.80 \n(127.80-270.70) pg/ml respectively, indicating a \nsignificant difference (P=0.003) (Figure 1). According \nto the FIGO classification, patients were categorized \ninto three different groups (grade I, II, and III) and the \nlevel of IL-27 was measured separately in each group \nand compared to the control ( Figure 2 ). The serum \nlevels of IL -27 in the group with grade I of EC was \n232.60 (176.93-325.09) pg/ml and in the Control group \n\nFatemeh Sedaghat et al. 660 \n      Volume 9, November – December 2024       Journal of Obstetrics, Gynecology and Cancer Research \nwas 204.80(127.80- 270.70) pg/ml, indicating no \nstatistically significant differences (P =0.10). While in \npatients with grade II, serum concentration of IL -27 \nwas 271.22(216.84- 346.64) pg/ml which showed \nsignificant differences in comparison with the control \n(P=0.006). In addition to patients with grade III of EC \nhad statistically higher serum levels of IL -27 in \ncomparison with the control group [271.10 (228.20-\n467.40) versus 204.8 (127.80- 270.70) pg/ml \nrespectively, P=0.01]. Regarding different EC grades, \nthere were no significant differences between grade I \nversus II (P=0.31), grade I versus III (P=0.35), or grade \nII versus III (P=0.88) (Table 2). \n To determine relation between IL -27 serum levels \nand demographic factors such as body mass index \n(BMI), menarche age and menopause age, Spearman's \nRho test was used which showed no substantial \nrelationships between serum levels of IL -27 and \nmentioned factors (P=0.48, P=0.95, P=0.51 \nrespectively) (Table 3) \n The ROC curve assessment ( Figure 3) revealed an \nAUC = 0.657, and 95% CI: 0.560 – 0.755. The optimal \ncut-off point of IL -27 for this differentia tion was \nestimated to be 212.42 pg/ml yielding a specificity of \n57% and a sensitivity of 70%.  \n \nTable 1. Demographic and clinicopathologic features of endometrial cancer patients and their associations with serum \nlevels of IL-27 \nVariables \nNumber \n(valid percent) \nIL-27 serum level \npg/ml \nP-value \nAge \n≤60 \nN=38 \n(58.5%) \n218.14(183.22-305.59) \n0.14 \n>60 \nN=27 \n(41.5%) \n274.36(200.02-388.85) \nTumor size \n≤ 3 cm \nN=39 \n(60%) \n256.85(176.93-346.64) \n0.54 \n˃3 cm \nN=26 \n(40%) \n283.24(196.63-355.40) \nLymph node \ninvolvement \nyes \nN=26 \n(40%) \n258.64(203.32-309.38) \n0.47 \nNo \nN=39 \n(60%) \n268.52(191.30-426.56) \n \nTumor \nGrade \nGrade I \n \nN=31 \n(47.7%) 232.60(176.93-325.09) \n0.42 \nGrade II \n \nN=20 \n(30.8%) 271.22(216.84-346.64) \nGrade III \n \nN=14 \n(21.5%) \n271.10(228.20– 467.40) \n \nTumor \nStage \n \nStage I \nN=40 \n(61.5%) \n273.64(178.29-356.79) \n0.79 \n \nStage II \nN=15 \n(23.1%) \n258.37(191.74-312.14) \n \nStage III \nN=10 \n(15.4%) \n264.72(201.17-321.52) \n \n \n \n\n661 L-27 Serum Levels in Endometrial Cancer \n      Volume 9, November – December 2024       Journal of Obstetrics, Gynecology and Cancer Research \nTable 2. The IL-27 serum levels in different grades of Endometrial Cancer \nGrade Frequency IL-27 serum level P-value \nII VS I 20(30.8%) VS 31(47.7%) \n271.22(216.84– 346.64) \nVS \n232.60(176.93 – 325.09) \n \n0.31 \nIII VS I 14 (21.5%) VS 31 (47.7%) \n271.10(228.20 – 467.40) \nVS \n232.60(176.93 – 325.09) \n \n0.35 \nIII VS II 14 (21.5%) VS 20 (30.8%) \n271.10(228.20– 467.40) \nVS \n271.22(216.84 – 346.64) \n0.88 \n \n \nTable 3. Correlation between demographic characteristics of endometrial cancer patients and serum IL-27 levels \nBMI Menarche age Menopause age Spearman's Rho \n0.089 0.007 -0.1 correlation coefficient \n0.48 0.95 0.51 P \n \n \n \nFigure 1. The serum levels of IL -27 in EC patients demonstrated a remarkable increase compared with the healthy \ncontrol group. \n \nP=0.003 \n\nFatemeh Sedaghat et al. 662 \n      Volume 9, November – December 2024       Journal of Obstetrics, Gynecology and Cancer Research \n \nFigure 2. The IL-27 serum levels in different grades of Endometrial Cancer. \n \n \n \nFigure 3. Area under the ROC curve analysis to determine the value of IL-27 in predicting Endometrial Cancer. \n \nDiscussion \nIn the present study, we observed that the serum level \nof IL -27 dramatically increased in EC patients \ncompared to healthy control group. Furthermore, in \nhigher grades (grade II and grade III) higher \nconcentrations of IL -27 were detected in comparison \nwith control group.  \nAlthough, several studies revealed the immune -\nregulatory effect of IL -27 in cancers and autoimmune \ndisorders, its exact function is still controversial and \ncomplex. In the last decade, our knowledge about IL -\n27 has changed from a cytokine t hat just induced Th1 \ncell response to one that has a both pro- inflammatory \nand anti -inflammatory effect. It appears that in early \nphases of inflammation process IL -27 induces \ninflammatory reaction, while in the late phases, by \ninfluencing various immune ce lls, it returns the \nimmune reaction to homeostasis (29). \n    P \n=0.10 \n           P=0.006 \n                    P=0.01 \n\n663 L-27 Serum Levels in Endometrial Cancer \n      Volume 9, November – December 2024       Journal of Obstetrics, Gynecology and Cancer Research \n IL-27 was initially identified as a pro -inflammatory \ncytokine that promoted the development of Th1 cells \nfrom naïve T cells (20). On the other hand, in some \ncircumstances IL -27 has a role in develop ment of \ninduced regulatory T lymphocytes (iTreg) with high \nIL-10 production capability (30, 31) , as well as \ntransformation of dendritic cells into \nimmunosuppressive phenotype by induction of B7- H1 \nexpression (32). Furthermore, IL -27 can promote IL -\n10 producing Tr1 cells from both human and mouse T \ncells and act in a negative feedback process against pro-\ninflammatory immune responses to favor tumor growth \n(33, 34). Diakowska group observed that serum IL -27 \nlevels in patients with gastro-esophageal cancer (GEC) \nis substantially higher in comparison with healthy \ncontrols and patients with benign diseases of the upper \nparts of gastrointestinal (GI) tract (18). Lu et al  (19) \nrevealed that breast cancer patients had higher levels of \nVEGF and IL-27 than healthy controls. In their study, \nthe level of IL -27 was shown to be substantially \nassociated to clinical stage (19) . In the study by the \nGonin et al (35), evaluation of IL -27 expression in \nprimary cutaneous melanoma samples revealed \nabsence of IL -27 in benign pigment and non- invasive \nmelanoma lesions, but high expression of IL -27 in \nprimary invasive melanoma. They concluded that IL -\n27 expression was correl ated with disease \ndevelopment, but not regression of tumor in melanoma \n(35). IL-27 has also been demonstrated to play a key \nrole in antitumor activities. Hisada was the first one \nwho investigated the antitumor effects of IL-27 Hisada \net al (36). In C26 mur ine colon carcinoma model, the \nHisada et al. discovered that IL -27 has significant \ncapacities to promote tumor -specific antitumor \nfunction and protective immunity which is mediated by \nIFN-γ, CD8+Tcells and T -bet but not through STAT4 \n(36). The anticancer e ffects of IL -27 have been \ndiscovered to be mediated via direct tumor growth \nsuppression, activation of NK cells, antibody -\ndependent T or NKT  cell cytotoxicity, anti -\nangiogenesis effects and cyclooxygenase -2 (COX -2) \ninhibition (37). \nIt has also been shown that IL-27 acts as an antitumor \nfactor and suppresses tumor growth in various kinds of \ncancers including esophageal cancer (38) , acute \nmyeloid leukemia (39) , colorectal cancer (40) , head \nand neck squamous cell carcinoma (HNSCC) (41), and \nlung carcinoma cell  lines Ho et al  (42). According to \nSekar et al (43) study, apoptotic tumor cells inhibit DCs \nfrom developing cytotoxicity against living human \ntumor cells by inducing IL -27, therefore activating a \nTreg cell population (43).  \nThe role of IL-27 in gynecological diseases has been \nlimitedly studied, and its exact function and \nmechanism is unknown. It has been found that by \ninducing IFN-γ, IL-6, IL-12, HLA class I expression, \nand STAT3 -mediated apoptosis while reducing NF -\nκB1, TLR4 and ovarian tumor cell growth,  IL-27 can \ncreate an anticancer environment (44, 45). On the other \nhand, IL-27 may contribute to progression of ovarian \ncancer by increasing immune- regulatory molecules \nlike Programmed Death -Ligand (PD -L) 1 and \nindoleamine 2, 3- dioxygenase (IDO) in a STAT1  and \nSTAT3 dependent mechanism (46) . IL-27 could also \nplay a role in endometriosis. Chang et al. showed that \nIL-27 secreted by endometrial stromal cells and MQs \npromotes the progression of endometriosis by \npromoting the differentiation of IL-10+T helper (Th)17 \ncells (47).  \nStudies to find a reliable tumor marker to diagnose \nendometrial cancer are ongoing. On the other hand, \nthere is still a long way to go to understand the exact \nrole of IL -27 in endometrial cancer, so more \ninvestigations are needed. \n \nConclusion \nNone.  \n \nAcknowledgments \nThis work was supported by a grant from Shiraz \nUniversity of Medical Sciences (Grant no. 98 -01-01-\n21587). \n \nConflict of Interest \nThe authors declared that they have no conflicts of \ninterest. \n \n \n \n1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, \n2014. CA Cancer J Clin. 2014;64(1):9-29.  \n[DOI:10.3322/caac.21208] \n2. Amant F, Moerman P, Neven P, Timmerman D, \nVan Limbergen E, Vergote I. Endometrial cancer. \nLancet. 2005;366:491-505.  \n[DOI:10.1016/S0140-6736(05)67063-8] \n3. Bokhman JV. Two pathogenetic types of \nendometrial carcinoma. Gynecol Oncol.  1983; \n15(1):10-7. [ DOI:10.1016/0090-8258(83)90111-\n7] \n4. Passarello K, Kurian S, Villanueva V. \nEndometrial cancer: an overview of \npathophysiology, management, and care. 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Petretto A, Carbotti G, Inglese E, Lavarello C, \nPistillo MP, Rigo V, et al. Proteomic analysis \nuncovers common effects of IFN -γ and IL-27 on \nthe HLA class I antigen presentation machinery \nin human ca ncer cells. Oncotarget. 2016;7(45):  \n72518-36. [DOI:10.18632/oncotarget.12235] \n46. Carbotti G, Barisione G, Airoldi I, Mezzanzanica \nD, Bagnoli M, Ferrero S, et al. IL -27 induces the \nexpression of IDO and PD -L1 in human cancer \ncells. Oncotarget. 2015;6(41):43267-80.  \n[DOI:10.18632/oncotarget.6530] \n47. Chang K-K, Liu L-B, Jin L-P, Zhang B, Mei J, Li \nH, et al. IL-27 triggers IL-10 production in Th17 \ncells via a c -Maf/RORγt/Blimp-1 signal to \npromote the progression of endometriosis. Cell \n\nFatemeh Sedaghat et al. 666 \n      Volume 9, November – December 2024       Journal of Obstetrics, Gynecology and Cancer Research \nDeath Differ. 2017;8(3):e2666.  \n[DOI:10.1038/cddis.2017.95] \n \n \nHow to Cite This Article:  \nSedaghat, F., Shiravani, Z., Karimi, A. M., Haghshenas, M. R., Ghaderi, A., Fattahi, M. J. Clinicopathological \nImplications of Serum level of IL-27 in Endometrial Cancer Patients. J Obstet Gynecol Cancer Res. 2024;9(6):658-\n66. \nDownload citation:                             RIS | EndNote | Mendeley |BibTeX |","source_license":"CC0","license_restricted":false}