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首页> 外文期刊>Molecular and Cellular Biology >Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation
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Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation

机译：过氧化物酶体增殖物激活的受体α调节负责肝细胞增殖的MicroRNA介导的信号级联。

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Activation of peroxisome proliferator-activated receptor α (PPARα) leads to hepatocellular proliferation and liver carcinomas. The early events mediating these effects are unknown. A novel mechanism by which PPARα regulates gene expression and hepatocellular proliferation was uncovered. MicroRNA (miRNA) expression profiling demonstrated that activated PPARα was a major regulator of hepatic miRNA expression. Of particular interest, let-7C, an miRNA important in cell growth, was inhibited following 4-h treatment and 2-week and 11-month sustained treatment with the potent PPARα agonist Wy-14,643 in wild-type mice. let-7C was shown to target c-myc via direct interaction with the 3′ untranslated region of c-myc. The PPARα-mediated induction of c-myc via let-7C subsequently increased expression of the oncogenic mir-17-92 cluster; these events did not occur in Pparα-null mice. Overexpression of let-7C decreased c-myc and mir-17 and suppressed the growth of Hepa-1 cells. Furthermore, using the human PPARα-expressing mouse model, which is responsive to Wy-14,643 effects on β-oxidation and serum triglycerides but resistant to hepatocellular proliferation and tumorigenesis, we demonstrated a critical role for let-7C in liver oncogenesis. Wy-14,643 treatment did not inhibit let-7C or induce c-myc and mir-17 expression. These observations reveal a let-7C signaling cascade critical for PPARα agonist-induced liver proliferation and tumorigenesis.
机译：过氧化物酶体增殖物激活受体α（PPARα）的激活导致肝细胞增殖和肝癌。调解这些影响的早期事件是未知的。揭示了一种新的机制，PPARα调节基因表达和肝细胞增殖。 MicroRNA（miRNA）表达谱表明，活化的PPARα是肝脏miRNA表达的主要调节因子。特别令人感兴趣的是，在野生型小鼠中，用强效PPARα激动剂Wy-14,643进行4小时治疗以及2周和11个月持续治疗后，let-7C（一种对细胞生长重要的miRNA）被抑制。 let-7C被证明通过与c- myc 的3'非翻译区直接相互作用而靶向c- myc 。 PPARα通过let-7C诱导c- myc 的诱导随后增加了致癌mir-17-92簇的表达;这些事件在 Ppar α-null小鼠中没有发生。 let-7C的过表达降低c- myc 和mir-17并抑制Hepa-1细胞的生长。此外，使用表达PPARα的人类小鼠模型，该模型对Wy-14,643对β氧化和血清甘油三酸酯的反应有反应，但对肝细胞增殖和肿瘤发生具有抗性，我们证明let-7C在肝癌发生中起关键作用。 Wy-14643处理未抑制let-7C或诱导c- myc 和mir-17表达。这些发现揭示了let-7C信号级联对于PPARα激动剂诱导的肝增殖和肿瘤发生至关重要。

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