The role and gene expression profile of SOCS3 in colorectal carcinoma.

Xing Dong,Jing Wang,Bo Tang,Pei-Wu Yu,Shi-Yong Li,Yeng-Xue Hao,Ping-Yang Li

doi:10.18632/oncotarget.23477

Abstract

SOCS3 has been postulated to play a role in the occurrence and progression of malignancies. However, the relationship of SOCS3 with colorectal carcinoma remains poorly understood. The purpose of the study was to explore the role of SOCS3 in colorectal carcinoma and its underlying mechanisms. Protein and mRNA expression of SOCS3 in colorectal carcinoma and normal colorectal mucosa was detected using immunohistochemistry and real-time quantitative PCR. SOCS3 expression was significantly lower in colorectal carcinoma tissue than in normal colorectal mucosa, and was negatively correlated with tumor invasion depth, lymph node metastasis, differentiation degree, and TNM stage. A stably transfected colorectal carcinoma cell line (8348SOCS3) with high expression of SOCS3 was established. The effects of SOCS3 overexpression on the growth, proliferation, invasion and tumor formation of colorectal carcinoma cells were examined by CCK-8 assay, transwell method and tumorigenicity assays in nude mice. Then we found SOCS3 overexpression significantly decreased proliferation and invasion capability of 8348 cells in vitro and in vivo. Furthermore, the effect of SOCS3 overexpression on the gene expression profile of colorectal carcinoma cells was analyzed using human genome arrays. The results revealed 369 genes that were differentially expressed in 8348SOCS3 cells. 193 genes was significantly increased and 176 genes was significantly decreased. Bioinformatics analysis demonstrated that high SOCS3 expression affected multiple signaling pathways in colorectal carcinoma including TGF-β/Smads, NF-κB, and HIF-MAPK pathways. Especially for the TGF-β/Smads pathways, high SOCS3 expression could inhibit TGF-β1 expression and activate Smad4 expression. These data suggested that low expression of SOCS3 was associated with the occurrence and progression of colorectal carcinoma. SOCS3 protein may be a useful indicator for malignancy and prognosis of colorectal carcinoma and also a new target for gene therapy.

Highlights

Colorectal carcinoma (CRC) is one of the most common clinical gastrointestinal tumors and its prevalence is increasing annually [1, 2]
Research has shown that expression of suppressor of cytokine signaling (SOCS)-3 is decreased in many malignant tumor tissues and cell lines, such as head and neck squamous cell carcinoma, liver cancer, renal carcinoma, melanoma, and prostate cancer [11,12,13]. whereas demethylation or recovery of SOCS-3 expression via approaches such as drug treatment can significantly inhibit the growth of tumor cells, suggesting that SOCS-3 may act as a tumor suppressor gene
SOCS3 is a member of the suppressor of cytokine signaling family and an important inhibitor of the JAK2/STAT3 signaling pathway

Summary

Introduction

Colorectal carcinoma (CRC) is one of the most common clinical gastrointestinal tumors and its prevalence is increasing annually [1, 2]. The suppressor of cytokine signaling (SOCS) family plays a key role in regulating the growth and differentiation of cells. Numerous studies have shown that SOCS3 expression can be induced by a variety of pro- and anti-inflammatory cytokines It can suppresses the signaling of multiple immune molecules. Since it exerts key roles in the development of inflammatory diseases, viral infections, obesity and cancer, SOCS3 may be a biomolecular indicator for disease diagnosis and prognostic prediction. It is serve as a potential target for the treatment of a variety of diseases [9, 10]. Research has shown that expression of SOCS-3 is decreased in many malignant tumor tissues and cell lines, such as head and neck squamous cell carcinoma, liver cancer, renal carcinoma, melanoma, and prostate cancer [11,12,13]. whereas demethylation or recovery of SOCS-3 expression via approaches such as drug treatment can significantly inhibit the growth of tumor cells, suggesting that SOCS-3 may act as a tumor suppressor gene

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