Immunology division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, 3001 North 12th avenue, Sherbrooke QC J1H 5N4, Canada.
Curr Pharm Des. 2014;20(17):2922-33. doi: 10.2174/13816128113199990597.
The SOCS1 gene is a frequent target of epigenetic repression in hepatocellular carcinoma. Many other types of cancer also harbor methylated SOCS1 gene. Besides, recent studies implicate microRNAs targeting SOCS1 in cancer progression. These findings suggest a broad tumor suppressor role of SOCS1 and have stimulated the quest to elucidate the underlying molecular mechanisms. The essential physiological function of SOCS1 is to attenuate interferon gamma signaling in immune cells. SOCS1 binds activated JAK kinases and the receptor chains of several cytokines, some of which are implicated in cancer progression. SOCS1 also facilitates ubiquitination and proteasomal degradation of many signaling molecules downstream of cytokine and growth factor receptors. We have shown that SOCS1 inhibits signaling via the hepatocyte growth factor receptor c-MET in hepatocytes. Aberrant MET signaling, implicated in the progression of many types of cancers, also contributes to the development of chemoresistance to tyrosine kinase inhibitors and drugs targeting other oncogenic signaling pathways. Here, we discuss the SOCS1-dependent regulation of MET signaling as an important mechanism underlying the tumor suppressor role of SOCS1 that is relevant not only to hepatocellular carcinoma but also to other types of cancers.
SOCS1 基因是肝细胞癌中表观遗传抑制的常见靶点。许多其他类型的癌症也存在甲基化 SOCS1 基因。此外，最近的研究表明，miRNA 靶向 SOCS1 在癌症进展中起作用。这些发现表明 SOCS1 具有广泛的肿瘤抑制作用，并激发了对其潜在分子机制的探索。SOCS1 的基本生理功能是在免疫细胞中减弱干扰素 γ 信号。SOCS1 结合激活的 JAK 激酶和几种细胞因子的受体链，其中一些与癌症进展有关。SOCS1 还促进细胞因子和生长因子受体下游许多信号分子的泛素化和蛋白酶体降解。我们已经表明，SOCS1 在肝细胞中抑制肝细胞生长因子受体 c-MET 的信号。异常的 MET 信号，涉及多种类型癌症的进展，也导致对酪氨酸激酶抑制剂和针对其他致癌信号通路的药物的耐药性发展。在这里，我们讨论了 SOCS1 依赖性的 MET 信号调节作为 SOCS1 的肿瘤抑制作用的重要机制，这不仅与肝细胞癌有关，而且与其他类型的癌症有关。
