Chu Qinjun, Shen Dan, He Long, Wang Hongwei, Liu Chunlan, Zhang Wei
Department of Anesthesiology, Zhengzhou University Affiliated First Hospital, 450052, He Nan, China.
Department of Anesthesiology, Zhengzhou University Affiliated First Hospital, 450052, He Nan, China.
Gene. 2017 Sep 5;627:114-122. doi: 10.1016/j.gene.2017.06.013. Epub 2017 Jun 8.
Colorectal cancer (CRC) is a common malignant tumor, in which the inflammatory microenvironment plays an important role. STAT3 signaling pathway is regarded as the "bridge" between inflammation and cancer, and involved in the development of CRC. SOCS3 is a key negative feedback regulator of JAK/STAT signaling pathway. Studies about SOCS3 gene in CRC are rarely reported. The purpose of this study is to determine the expression of SOCS3 in CRC tissue and its correlation with the clinical pathological characteristics and prognosis of colorectal cancers. The effects of SOCS3 on biological behavior such as apoptosis, proliferation, migration, invasion and tumor formation in nude mice were studied. We observed that SOCS3 expression was down-regulated in CRC tissues, while IL-6, pSTAT3 were up-regulated. Inflammatory cytokines IL-6 can promote the expression of STAT3 signaling pathways while inhibit the expression of SOCS3 by promoting hypermethylation of SOCS3 gene promoters. 5-Aza-cdR treatment can reverse IL-6/STAT3 signaling pathway mediated down-regulation of SOCS3 in colorectal cancer cells. Low expression of SOCS3 was correlated with lymph node metastasis and advanced clinical stage. Patients with high expression of SOCS3 in colorectal cancers often indicated a relatively good prognosis. Overexpression of SOCS3 inhibited proliferation, migration, invasion and tumorigenic ability of CRC cells while increased cell apoptosis. This study demonstrated that IL-6/STAT3 signaling activation negatively regulated SOCS3 expression, which led to imbalance and sustained activation of STAT3 signaling pathway. Reduced expression of SOCS3 promoted the growth and metastasis of colorectal cancer. Thus, targeting IL-6/STAT3/SOCS3 signaling pathway may become an important treatment strategy of colorectal cancer.
结直肠癌（CRC）是一种常见的恶性肿瘤，其中炎症微环境起着重要作用。STAT3信号通路被视为炎症与癌症之间的“桥梁”，并参与结直肠癌的发生发展。SOCS3是JAK/STAT信号通路的关键负反馈调节因子。关于结直肠癌中SOCS3基因的研究报道较少。本研究旨在确定SOCS3在结直肠癌组织中的表达及其与结直肠癌临床病理特征和预后的相关性。研究了SOCS3对裸鼠细胞凋亡、增殖、迁移、侵袭和肿瘤形成等生物学行为的影响。我们观察到，结直肠癌组织中SOCS3表达下调，而IL-6、pSTAT3表达上调。炎性细胞因子IL-6可促进STAT3信号通路表达，同时通过促进SOCS3基因启动子的高甲基化抑制SOCS3表达。5-氮杂胞苷（5-Aza-cdR）处理可逆转IL-6/STAT3信号通路介导的结直肠癌细胞中SOCS3的下调。SOCS3低表达与淋巴结转移及临床晚期相关。结直肠癌中SOCS3高表达的患者通常预后相对较好。SOCS3过表达抑制结直肠癌细胞的增殖、迁移、侵袭和致瘤能力，同时增加细胞凋亡。本研究表明，IL-6/STAT3信号激活负向调节SOCS3表达，导致STAT3信号通路失衡并持续激活。SOCS3表达降低促进了结直肠癌的生长和转移。因此，靶向IL-6/STAT3/SOCS3信号通路可能成为结直肠癌的重要治疗策略。
