MicroRNA-196a / -196b通过靶向SOCS2调节JAK / STAT通路来调节肝细胞癌的进展。,Cell Death & Disease

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MicroRNA-196a / -196b通过靶向SOCS2调节JAK / STAT通路来调节肝细胞癌的进展。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-04-15 , DOI: 10.1038/s41419-019-1530-4
Weihua Ren ₁ , Shuangting Wu ₂ , Yabin Wu ₁ , Tan Liu ₁ , Xingpeng Zhao ₁ , Yawei Li ₃

Affiliation

microRNA（miRNA）在肝细胞癌（HCC）的进展中起重要作用。但是，关于miR-196a和miR-196b的作用以及在肝癌进展中的机制仍然知之甚少。通过定量实时聚合酶链反应或免疫组织化学方法检测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，凋亡和坏死研究了肝癌的进展。通过荧光素酶活性和RNA免疫沉淀分析探索了SOCS2与miR-196a或miR-196b之间的相互作用。Western blot检测Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径中蛋白质的表达。建立异种移植模型以研究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，肿瘤淋巴结转移阶段，淋巴结转移，白蛋白-胆红素等级和不良5年生存率相关。抑制miR-196a或miR-196b可抑制细胞增殖，糖酵解，细胞周期过程，集落形成，但可诱导HCC细胞凋亡或坏死。SOCS2被miR-196a和miR-196b靶向，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，敲低miR-196a或miR-196b可以通过阻断JAK / STAT通路来限制异种移植瘤的生长。

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MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2.

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.

更新日期：2019-04-15

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