Prognostic Value Of IL-6R MRNA In Ovarian Cancer,Lung Cancer And Breast Cancer

BackgroundTumor is the world's major public health problem and results in a serious problem to global health.Tumor microenvironment is a pathological environment of tumor cells which can promote tumor progression and cell metastasis.Interleukin-6/interleukin-6 receptor(IL-6/IL-6R)signaling pathwayhas a wide range of biological activity in the normal body balance and immune responseand plays a significant role in tumor progression.At present,a number of studies have described the prognostic value of IL-6 in a variety of tumors,and even several clinical trials.It is known that IL-6 must bind to IL-6R and then transmit signals through gp130 to the cells.However,there were rarely studies that explain the prognostic value of IL-6R in those tumors.This study aimed to explore the potential clinical and biological functions of IL-6R mRNA in ovarian cancer,lung cancer and breast cancer.Objective1.To reveal the prognostic effect of IL-6R mRNA in ovarian cancer,lung cancer and breast cancer;2.To explore the relationship between the mRNA expression of IL-6 and IL-6R,the relationship between IL-6 and gp130,and between IL-6R and gp130 in each tumor;3.To explore the most important biological processes and pathway that IL-6R mRNA and its most related genes were enriched in;4.To explore the different biological function of IL-6R mRNA in different tumors.Materials and Methods1.Electronic databases were searched through GEO databaseusing the keywords"ovarian cancer","lung cancer" and "breast cancer".The included criteria of data were(1)the organism is homo sapiens;(2)entry type is series;(3)the sample size is greater than or equal to 100;(4)information of survival time and survival status was included;(5)the public microarray data contains IL-6R mRNA.At the same time,the corresponding TCGA dataset for each tumor was included.2.We extract all the key information in all datasets.When several metric variables correspond to the same gene,the mean was taken as the expression value of the gene.We used the Cutoff Finder website to select an appropriate cutoff value and stratify patients into two groups.3.Univariate and multivariate Cox proportional hazards model was done for each independent data set.The hazard ratio(HR)and 95%confidence interval(95%CI)were calculated to measure the effective prognostic value of expression of IL-6RmRNA.Pooled HR and related analyses were carried out using STATA software package(version 12.0).4.In this study,we analyzed the correlation between IL-6,IL-6R and gp130.Pooled correlation was calculated based on Fisher's z transformation using metacor function in meta package in R software.5.For each dataset,we calculated the correlation coefficient between IL-6R and the remaining genes,and then matched the coefficients in all datasets.Genes with absolute correlation coefficient which were greater than 0.3 or 0.4 in half of or more publications were extracted.Functional enrichment analysis of IL-6R and its related genes was done onthe Database for Annotation,Visualization and Integrated Discovery(DAVID)(https://david.ncifcrf.gov/summary.jsp).Results1.A total of 8 related ovarian cancer publications were included in this study.Pooled HR was 0.62,95%CI were(0.45,0.86)in univariate analysis.Pooled HR was 0.63 and 95%CI was(0.45,0.86)in multivariate analysis.2.There was no statistically significant association between IL-6 and IL-6Ror between IL-6R and gp130 in ovarian cancer.There was a positive correlation between IL-6 and gp130(r = 0.225,P<0.001).The pooled correlation coefficients for IL-6 and gp130 was higher in patients with higher IL6R expression than patients with lower IL6R expression(pooled r = 0.310,P<0.001 vs.pooled r = 0.182,P<0.001).3.One hundred sixteen genes which absolute correlation coefficients were greater than 0.3 in three or more publications were extracted in ovarian cancer.Functional enrichment analysis on IL-6R and the most related genes shown that the most significant biological processes was inflammatory response and immune response.Bacteria and viruses infections are also included4.There were 8 datasets and 6 datasets for lung adenocarcinoma and squamous cell carcinoma analysis.For lung adenocarcinoma,pooled HR was 0.50,95%CI were(0.33,0.68)in univariate analysis;pooled HR was 0.50;95%CI were(0.35,0.73)in multivariate analysis.5.IL-6 and IL-6R were negatively correlated with lung adenocarcinoma(r =-0.199,P<0.001),while positively correlated with lung squamous cell carcinoma(r = 0.288,P<0.001).IL-6R and gp130 were positively correlated in both lung adenocarcinoma and squamous cell carcinoma,and the correlation coefficient was similar(r = 0.332 in lung adenocarcinoma,r = 0.334 in lung squamous cell carcinoma).6.One hundred ninety three genes which absolute correlation coefficients were greater than 0.4 in four or more publications were extracted in lung adenocarcinoma and they were most involved in cell cycle.One hundredand one genes were extracted in lung squamous cell carcinoma and these genes were mainly enriched in cell proliferation,natural killer cell mediated cytotoxicity and so on.7.Seventeen breast cancer datasets were included in the study.Pooled HR was 0.66 and 95%CI were(0.45,0.95)in univariate analysis,pooled HR was 0.54,95%CI were(0.37,0.78)in multivariate analysis.8.There was no statistically significant association between IL-6 and gpl30 or between IL-6R and gp130 in breast cancer.However,there was a positive correlation between IL-6 and IL-6R(r = 0.198,P<0.001).9.One hundred thirty-nine genes which absolute correlation coefficients were greater than 0.4 in eight or more datasets were extractedand they were most involved inB cell receptor signaling pathway,inflammatory response,immune response,and Regulation of platelet aggregation and T cell differentiation.Conclusion1.The expression level of IL-6R mRNA in ovarian cancer,lung adenocarcinoma and breast cancer tissues is significantly related to the prognosis of patients.The higher the level of IL-6R mRNA is,the better prognosis the patients have.And it can be used as the prognostic marker of these cancers.There was no significant association in lung squamous cell carcinoma.However,the lower limit of 95%confidence interval is close to 1.00(0.98).As the sample size in lung squamous cell carcinoma is small in each dataset,the conclusion should be validated by data with a larger sample size.2.The most important biological processes of IL-6R and its related genes were different in different tumors or different subtypes of the tumor.And the correlations between IL-6,IL-6R and gp130,prognostic value of IL-6R mRNA in those tumors were also different.3.The number of datasets included in the study was different.Especially in the lung squamous cell carcinoma dataset,the number of relative datasets was small,and the number of samples size in each dataset was also small.More data that containing a variety of important clinical parameters,especially chemotherapy,are needed to further validate and explore the relationship between IL-6R mRNA and clinical parameters.