Androgen pathway stimulates MicroRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis
Androgen pathway stimulates MicroRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis
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DOI：
10.1002/hep.25695
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发表时间：
2012-08-01
期刊：
影响因子：
13.5
通讯作者：
Chen, Pei-Jer
中科院分区：
文献类型：
--
作者：
Chen, Po-Jen;Yeh, Shiou-Hwei;Chen, Pei-Jer
microRNA (miRNA) 失调在晚期人类肝细胞癌 (HCC) 中很常见；然而，尚未对参与早期致癌作用的因素进行研究。通过检测癌前和癌变肝组织之间 22 个 HCC 相关 miRNA 的表达，我们发现 miR-216a 和 miR-224 从癌前阶段开始显着上调。此外，miR-216a 的升高主要见于男性患者。为了研究这种性别差异，我们证明 pri-miR-216a 以配体依赖性方式被雄激素途径转录激活，并被乙型肝炎病毒 X 蛋白进一步增强。划定了 pri-miR-216a 的转录起始位点，并在其启动子区域内鉴定了一个假定的雄激素反应元件位点。该位点的突变消除了雄激素途径对 pri-miR-216a 的升高。 miR-216a 的一个靶点被证明是肺癌 1 基因 (TSLC1) 信使 RNA (mRNA) 中的肿瘤抑制因子，通过其 3' 非翻译区的三个靶位点。最后，从癌前阶段开始，在肝癌发生过程中，男性肝组织中的雄激素受体水平增加，伴随着miR-216a的升高，但TSLC1的降低。结论：本研究发现雄激素途径上调miRNA-216a并随后抑制TSLC1是早期肝癌发生中雄激素途径的新机制。 （肝病学 2012）
Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC-related miRNAs between precancerous and cancerous liver tissues, we found miR-216a and miR-224 were significantly up-regulated, starting from the precancerous stage. Furthermore, the elevation of miR-216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri-miR-216a is activated transcriptionally by the androgen pathway in a ligand-dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri-miR-216a was delineated, and one putative androgen-responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri-miR-216a by the androgen pathway. One target of miR-216a was shown to be the tumor suppressor in lung cancer-1 gene (TSLC1) messenger RNA (mRNA) through the three target sites at its 3' untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR-216a but a decrease of TSLC1. Conclusion: The current study discovered the up-regulation of miRNA-216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (HEPATOLOGY 2012)