Effects of MicroRNA-29 on Apoptosis, Tumorigenicity, and Prognosis of Hepatocellular Carcinoma
Effects of MicroRNA-29 on Apoptosis, Tumorigenicity, and Prognosis of Hepatocellular Carcinoma
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microRNA-29对肝细胞癌凋亡、致瘤性和预后的影响
DOI：
10.1002/hep.23380
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发表时间：
2010-03-01
期刊：
影响因子：
13.5
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Xiong, Yujuan;Fang, Jian-Hong;Zhuang, Shi-Mei
基于微阵列数据，我们之前已经发现miR-29在肝细胞癌（HCC）组织中显著下调。迄今为止，miR-29失调在肝癌发生中的作用以及miR-29发挥其功能和调节HCC细胞恶性表型的信号通路在很大程度上仍然未知。在本研究中，我们使用Northern blot和实时定量逆转录聚合酶链反应证实了miR-29表达降低是HCC组织中常见的事件。更有趣的是，我们发现miR-29下调与HCC患者更差的无病生存期显著相关。两项功能获得和功能缺失的研究都表明，miR-29可以使HCC细胞对血清饥饿和缺氧或化疗药物引发的凋亡敏感，从而模拟体内肿瘤生长环境和临床治疗。此外，miR-29的引入显著抑制了裸鼠HCC细胞形成肿瘤的能力。随后的研究发现，两种抗凋亡分子Bcl-2和Mcl-1是miR-29的直接靶点。此外，Bcl-2和Mcl-1的沉默表型化了miR-29的促凋亡作用，而这些蛋白的过表达减弱了miR-29的作用。此外，miR-29表达增强导致线粒体电位丧失，细胞色素c向细胞质释放，提示miR-29可能通过涉及Mcl-1和Bcl-2的线粒体途径促进细胞凋亡。结论：我们的数据强调了miR-29在细胞凋亡调控和HCC分子病因学中的重要作用，并暗示了miR-29在预后预测和癌症治疗中的潜在应用。(肝脏病学51:836 2010;845)。
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;51:836-845.)