miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway.
miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway.
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DOI：
10.18632/oncotarget.2905
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Xu X;Chen W;Miao R;Zhou Y;Wang Z;Zhang L;Wan Y;Dong Y;Qu K;Liu C
越来越多的证据表明，miRNAs既可以作为肿瘤抑制因子，也可以作为癌基因参与肿瘤的发生。在本研究中，我们确定了miR-34 a在调节端粒酶活性中的作用，以及随后对细胞衰老和活力的影响。我们发现miR-34 a的高表达与肝细胞癌的晚期临床病理参数显著相关。此外，75例HCC患者的肿瘤组织显示miR-34 a水平与端粒指数（端粒长度和端粒酶活性）之间呈负相关。瞬时导入miR-34 a可抑制肝癌细胞端粒酶活性和端粒长度，诱导细胞衰老样表型，影响细胞活力。我们发现miR-34 a有效地靶向c-Myc和FoxM 1，这两者都参与了端粒酶逆转录酶（hTERT）转录的激活，这对维持端粒酶活性以避免衰老至关重要。综上所述，我们的研究结果表明，miR-34 a作为一种有效的肿瘤抑制剂，通过调节端粒途径在细胞衰老。
Increasing evidence suggests that miRNAs can act as either tumor suppressors or oncogenes in carcinogenesis. In the present study, we identified the role of miR-34a in regulating telomerase activity, with subsequent effect on cellular senescence and viability. We found the higher expression of miR-34a was significantly correlated with the advanced clinicopathologic parameters in hepatocellular carcinoma. Furthermore, tumor tissues of 75 HCC patients demonstrated an inverse correlation between the miR-34a level and telomere indices (telomere length and telomerase activity). Transient introduction of miR-34a into HCC cell lines inhibited the telomerase activity and telomere length, which induced senescence-like phenotypes and affected cellular viability. We discovered that miR-34a potently targeted c-Myc and FoxM1, both of which were involved in the activation of telomerase reverse transcriptase (hTERT) transcription, essential for the sustaining activity of telomerase to avoid senescence. Taken together, our results demonstrate that miR-34a functions as a potent tumor suppressor through the modulation of telomere pathway in cellular senescence.
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