Jin Yun, Wang Junfeng, Han Jiang, Luo Ding, Sun Zhiwei
Departement of Hepatobiliary Surgery, The First People's Hospital of Yunnan Province, Kunming 650030, Yunnan, China.
Departement of Hepatobiliary Surgery, Kunming General Hospital, PLA, Kunming 650032, Yunnan, China.
Exp Cell Res. 2017 Nov 15;360(2):210-217. doi: 10.1016/j.yexcr.2017.09.010. Epub 2017 Sep 8.
The downregulation of microRNA-122 (miR-122) had been reported to be associated with tumor invasion and metastasis in hepatocellular carcinoma (HCC). However, the underlying mechanisms of miR-122 involved in epithelial-mesenchymal transition (EMT) still need to be investigated. In the study, we demonstrated that miR-122 was significantly downregulated in HCC tissues compared with adjacent normal tissues. MiR-122 expression was closely correlated with tumor size, vascular invasion and American Joint Committee on Cancer (AJCC) stage of HCC patients. Kaplan-Meier survival curve and log rank test demonstrated that lower miR-122 predicted poor Disease-free survival (DFS) and overall survival (OS) time in patients. Univariate and multivariate Cox analysis confirmed that tumor size, vascular invasion, American Joint Committee on Cancer (AJCC) stage and lower miR-122 expression levels were independent risk factors for DFS or OS in HCC patients. Function assays demonstrated that upregulation of miR-122 inhibited the cell proliferation, colony formation and cell invasion in HCC cells, however, downregulation of miR-122 promoted cell proliferation, colony formation and cell invasion in HCC cells. Moreover, we demonstrated that increased miR-122 expression levels in HCC cells inhibited epithelial-mesenchymal transition (EMT) by suppressing the expression of ZEB1/2, Snail1/2, N-cadherin, Vimentin and upregulating the E-cadherin expression. However, downregulation of miR-122 caused an opposite effects. Mechanisms study found that miR-122 overexpression inhibited the EMT process by targeting Snail1 and Snail2 and regulated their expression levels in HCC cells. In addition, we also revealed that upregulated miR-122 expression suppressed the Wnt/β-catenin signaling pathway. Taken together, our results indicated that miR-122 may be a biomarker for predicting prognosis of HCC and therapeutic target for HCC patients.
据报道，微小RNA-122（miR-122）的下调与肝细胞癌（HCC）的肿瘤侵袭和转移有关。然而，miR-122参与上皮-间质转化（EMT）的潜在机制仍有待研究。在本研究中，我们发现与癌旁正常组织相比，miR-122在HCC组织中显著下调。miR-122的表达与HCC患者的肿瘤大小、血管侵犯及美国癌症联合委员会（AJCC）分期密切相关。Kaplan-Meier生存曲线和对数秩检验表明，较低的miR-122预示着患者无病生存期（DFS）和总生存期（OS）较差。单因素和多因素Cox分析证实，肿瘤大小、血管侵犯、AJCC分期及较低的miR-122表达水平是HCC患者DFS或OS的独立危险因素。功能实验表明，上调miR-122可抑制HCC细胞的增殖、集落形成及细胞侵袭，而下调miR-122则促进HCC细胞的增殖、集落形成及细胞侵袭。此外，我们还发现，HCC细胞中miR-122表达水平的升高通过抑制ZEB1/2、Snail1/2、N-钙黏蛋白、波形蛋白的表达及上调E-钙黏蛋白的表达来抑制上皮-间质转化（EMT）。然而，下调miR-122则产生相反的效果。机制研究发现，miR-122过表达通过靶向Snail1和Snail2抑制EMT过程，并调节其在HCC细胞中的表达水平。此外，我们还发现上调miR-122表达可抑制Wnt/β-连环蛋白信号通路。综上所述，我们的结果表明，miR-122可能是预测HCC预后的生物标志物及HCC患者的治疗靶点。
