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【转帖】MicriRNA-29对肝细胞癌凋亡、致瘤性和预后的影响
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Effects of MicroRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma Based on microarray data, we have previously shown a significant down-regulation of miR-29 in hepatocellular carcinoma (HCC) tissues. To date, the role of miR-29 deregulation in hepatocarcinogenesis and the signaling pathways by which miR-29 exerts its function and modulates the malignant phenotypes of HCC cells remain largely unknown. In this study, we confirmed that reduced expression of miR-29 was a frequent event in HCC tissues using both Northern blot and real-time quantitative reverse-transcription polymerase chain reaction. More interestingly, we found that miR-29 down-regulation was significantly associated with worse disease-free survival of HCC patients. Both gain- and loss-of-function studies revealed that miR-29 could sensitize HCC cells to apoptosis that was triggered by either serum starvation and hypoxia or chemotherapeutic drugs, which mimicked the tumor growth environment in vivo and the clinical treatment. Moreover, introduction of miR-29 dramatically repressed the ability of HCC cells to form tumor in nude mice. Subsequent investigation characterized two antiapoptotic molecules, Bcl-2 and Mcl-1, as direct targets of miR-29. Furthermore, silencing of Bcl-2 and Mcl-1 phenocopied the proapoptotic effect of miR-29, whereas overexpression of these proteins attenuated the effect of miR-29. In addition, enhanced expression of miR-29 resulted in the loss of mitochondrial potential and the release of cytochrome c to cytoplasm, suggesting that miR-29 may promote apoptosis through a mitochondrial pathway that involves Mcl-1 and Bcl-2. Conclusion: Our data highlight an important role of miR-29 in the regulation of apoptosis and in the molecular etiology of HCC, and implicate the potential application of miR-29 in prognosis prediction and in cancer therapy. (HEPATOLOGY 2010.) |
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MicriRNA-29对肝细胞癌凋亡、致瘤性和预后的影响 基于微阵列资料，我们以前研究发现miR-29在肝细胞癌中明显下调。到目前为止，miR-29失调在肝细胞癌中作用，miR-29发挥作用和调控肝细胞癌细胞恶性表型的信号通路还不清楚。在该项研究中，我们应用Northern blot和实时定量RT-PCR方法证实miR-29低表达是肝细胞癌组织中一个常见的事件。比较有兴趣的是，miR-29下调明显与HCC病人无疾病生存差明显相关。功能获得和丧失研究显示miR-29可能是通过饥饿、缺氧或化疗药物触发了HCC细胞发生凋亡，这模拟了肿瘤体内生长环境和临床治疗。而且，miR-29可显著抑制HCC 细胞在裸鼠形成肿瘤的能力。随后的研究发现2种凋亡分子bcl-2和Mcl-1可作为miR-29的直接靶点。而且，沉默bcl-2和Mcl-1表型模拟了miR-29的前凋亡效应，而这些蛋白的过表达则消弱了miR-29效应。另外，miE-29增强的表达可导致线粒体潜能的丧失和细胞色素c释放到胞质中，提示miR-29可通过涉及Mcl-1和Bcl-2的线粒体途径而促进凋亡。结论：我们的资料表明miR-29在HCC凋亡调控和分子病因中的重要作用，提示miR-29在癌症的预后预测和治疗中潜在的作用。 |
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