MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2
MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2
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DOI：
10.1038/s41419-019-1530-4
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发表时间：
2019-04-15
影响因子：
9
通讯作者：
Li, Yawei
中科院分区：
文献类型：
--
作者：
Ren, Weihua;Wu, Shuangting;Li, Yawei
microRNAs （miRNAs）在肝细胞癌（HCC）的进展中起着重要作用。然而，miR-196a和miR-196b在HCC进展中的作用及其机制仍然知之甚少。采用实时定量聚合酶链反应或免疫组织化学检测HCC组织和细胞中miR-196a、miR-196b和细胞因子信号传导抑制因子2 （SOCS2）的表达。通过细胞增殖、糖酵解、周期、克隆、凋亡和坏死来研究HCC的进展。通过荧光素酶活性和RNA免疫沉淀分析，探讨了SOCS2与miR-196a或miR-196b之间的相互作用。western blot检测Janus kinase (JAK)/signal transducer and activator of transcription （STAT）通路蛋白的表达。建立异种移植物模型，研究miR-196a或miR-196b在体内的作用。我们发现miR-196a和miR-196b在HCC组织和细胞中高表达。miR-196a或miR-196b的高表达与肿瘤大小、肿瘤淋巴结转移分期、淋巴结转移、白蛋白-胆红素分级及5年生存率低相关。miR-196a或miR-196b的下调抑制HCC细胞的增殖、糖酵解、细胞周期过程和集落形成，但诱导细胞凋亡或坏死。miR-196a和miR-196b靶向SOCS2，其干扰消除了miR-196a或miR-196b介导的对HCC进展的抑制作用。SOCS2与JAK/STAT通路的激活呈负相关。此外，miR-196a或miR-196b的下调通过阻断JAK/STAT通路来限制异种移植物肿瘤的生长。我们得出结论，下调miR-196a或miR-196b通过靶向SOCS2调控JAK/STAT通路抑制HCC进展，为HCC的预后和治疗提供了新的靶点。
microRNAs (miRNAs) play essential roles in progression of hepatocellular carcinoma (HCC). However, the roles of miR-196a and miR-196b as well as mechanism in HCC progression remain poorly understood. The expressions of miR-196a, miR-196b and suppressor of cytokine signaling 2 (SOCS2) were measured in HCC tissues and cells by quantitative real-time polymerase chain reaction or immunohistochemistry. HCC progression was investigated by cell proliferation, glycolysis, cycle, clones, apoptosis, and necrosis. The interaction between SOCS2 and miR-196a or miR-196b was explored by luciferase activity and RNA immunoprecipitation analyses. The expressions of proteins in Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway were measured by western blot. A xenograft model was established to investigate the roles of miR-196a or miR-196b in vivo. We found that miR-196a and miR-196b were highly expressed in HCC tissues and cells. High expression of miR-196a or miR-196b was correlated with tumor size, tumor-node-metastasis stage, lymph node metastasis, albumin-bilirubin grade and poor 5-year survival. Knockdown of miR-196a or miR-196b suppressed cell proliferation, glycolysis, cell cycle process, colony formation but induced apoptosis or necrosis in HCC cells. SOCS2 was targeted by miR-196a and miR-196b and its interference ablated abrogation of miR-196a or miR-196b-mediated inhibitory effect on HCC progression. SOCS2 was negatively associated with activation of the JAK/STAT pathway. Besides, knockdown of miR-196a or miR-196b limited xenograft tumor growth by blocking the JAK/STAT pathway. We concluded that downregulation of miR-196a or miR-196b inhibited HCC progression through regulating the JAK/STAT pathway via targeting SOCS2, providing novel targets for prognosis and therapeutics of HCC.