Abstract
BackgroundAbnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA).MethodsThe gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA).ResultsData related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro.ConclusionsSOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer.
Highlights
Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers
Date extraction from GEPIA database Gene Expression Profiling Interactive Analysis (GEPIA) is a novel interactive web-based application, which was used for analyzing the gene expression datasets based on 9736 tumor and 8587 normal samples extracted from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases [15]
Regarding SOCS3 expression, 428 studies were considered, among which 30 showed increased expression and 42 showed decreased expression in tumor tissues compared with normal tissues
Summary
Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. The currently established clinical treatments for breast cancer mainly include surgery, radiotherapy, and chemotherapy [3]. The considerably high rates of recurrence and metastasis of breast cancer make the effects of its clinical treatment unsatisfactory, leading to generally poor patient prognosis [4, 5]. Since cytokine signaling plays an essential role in the initiation and development of human cancer, various studies have focused on elucidating the relationships between the expression of SOCS family members and different cancer types [8, 9]. It has been reported that the abnormal expression of SOCS proteins can regulate cancer development in various tumor cell types, as well as in immune cells in the tumor microenvironment [10]
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