TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3.
TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3.
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DOI：
10.1038/onc.2009.468
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发表时间：
2010-03-25
期刊：
影响因子：
8
通讯作者：
Ghoshal, K.
中科院分区：
文献类型：
--
作者：
Wang, B.;Hsu, S-H;Majumder, S.;Kutay, H.;Huang, W.;Jacob, S. T.;Ghoshal, K.
为了鉴定可能在肝癌发生中起因果作用的microRNA，我们使用了一种动物模型，其中喂食胆碱缺乏和氨基酸定义（CDAA）饮食的C57/BL 6小鼠在65周时发生肿瘤前病变，84周后发生肝细胞癌。miRNA表达谱显示，早在32周时，小鼠肝脏中的miR-181 b和miR-181 d就显着上调，并持续到肿瘤前阶段。TIMP 3（一种肿瘤抑制因子和经验证的miR-181靶点）的表达在喂食CDAA饲料的小鼠肝脏中受到显著抑制。在喂食CDAA饲料的小鼠中，肝TGFβ及其下游介质Smad 2、3和4的上调以及肝核提取物中磷酸化Smad 2的增加与miR-181 b/d升高相关。当肝细胞暴露于TGFβ时，前体和成熟miR-181 b的水平增加，并且通过siRNA介导的Smad 4消耗而显著降低，表明TGFβ信号通路参与miR-181 b表达。miR-181 b的异位表达和缺失表明，miR-181 b可增强MMP 2和MMP 9的活性，促进HCC细胞的生长、克隆形成、迁移和侵袭，而这一作用可通过调节TIMP 3水平而逆转。此外，miR-181 b的耗尽抑制了裸鼠中HCC细胞的肿瘤生长。miR-181 b还增强了HCC细胞对抗癌药物阿霉素的抗性。基于这些结果，我们得出结论，在喂食CDAA饮食的早期阶段，miR-181 b的上调促进了肝癌的发生。
To identify microRNAs that may play a causal role in hepatocarcinogenesis, we used an animal model in which C57/BL6 mice fed choline deficient and amino acid defined (CDAA) diet develop preneoplastic lesions at 65 weeks and hepatocellular carcinomas after 84 weeks. miRNA expression profiling showed significant upregulation of miR-181b and miR-181d in the livers of mice as early as 32 weeks that persisted at preneoplastic stage. The expression of TIMP3, a tumor suppressor and a validated miR-181 target, was markedly suppressed in the livers of mice fed CDAA diet. Upregulation of hepatic TGFβ and its downstream mediators Smad 2, 3 and 4 and increase in phospho-Smad2 in the liver nuclear extract correlated with elevated miR-181b/d in mice fed CDAA diet. The levels of the precursor and mature miR-181b were augmented upon exposure of hepatic cells to TGFβ and were significantly reduced by siRNA-mediated depletion of Smad4, demonstrating the involvement of TGFβ signaling pathway in miR-181b expression. Ectopic expression and depletion of miR-181b showed that miR-181b enhanced MMP2 and MMP9 activity and promoted growth, clonogenic survival, migration and invasion of HCC cells that could be reversed by modulating TIMP3 level. Further, depletion of miR-181b inhibited tumor growth of HCC cells in nude mice. miR-181b also enhanced resistance of HCC cells to the anti-cancer drug doxorubicin. Based on these results, we conclude that upregulation of miR-181b at early stages of feeding CDAA diet promotes hepatocarcinogenesis.
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