MicroRNA-191 Acts as a Tumor Promoter by Modulating the TET1-p53 Pathway in Intrahepatic Cholangiocarcinoma
MicroRNA-191 Acts as a Tumor Promoter by Modulating the TET1-p53 Pathway in Intrahepatic Cholangiocarcinoma
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DOI：
10.1002/hep.29116
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发表时间：
2017-07-01
期刊：
影响因子：
13.5
通讯作者：
Zhang, Zheng-Yun
中科院分区：
文献类型：
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作者：
Li, Hao;Zhou, Zun-Qiang;Zhang, Zheng-Yun
由于对 ICC 致癌机制的了解尚不清楚，目前对肝内胆管癌 (ICC) 的治疗仍然无效。越来越多的证据表明，包括 miR-191 在内的 microRNA (miRNA) 在肿瘤发生中发挥着重要作用。但 miR-191 在 ICC 中的表达和生物学功能仍有待确定。本研究探讨了 miR-191 在 ICC 中的功能和潜在机制。在五对 ICC 中生成 ICC miRNA 图谱，并通过新一代测序技术与正常胆管组织进行匹配；通过定量 RT-PCR 验证了 18 对 ICC 组织和正常胆管组织中的 ICC miRNA 谱。在体外和体内研究了 ICC 中 miR-191 相关的机制，并在 84 名患者中与 miR-191 相关的临床结果相关。我们的结果显示，与邻近的正常胆管组织相比，ICC 中 miR-191 的表达显着增加（P < 0.001）。 miR-191的过度表达促进胆管癌细胞的体外和体内增殖、侵袭和迁移。 miR-191 表达升高降低了 10-11 易位 1 (TET1) 的表达水平，TET1 是 ICC 中 miR-191 的直接靶基因，可催化去甲基化。 TET1表达水平降低使得p53基因转录起始位点的富含CpG的甲基化区域保持甲基化，导致p53表达水平降低，从而损害p53的抗癌活力。最后，发现miR-191是ICC患者预后不良的独立危险因素（总生存，风险比= 3.742，95％置信区间2.080-6.733，P < 0.001；无病生存，风险比= 2.331，95％置信区间1.346-4.037，P = 0.003）。结论：我们的结果表明，过表达的 miR-191 通过 miR-191/TET1/p53 途径与 ICC 进展相关。
Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). Conclusion: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway.