miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway
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Xinsen Xu1, Wei Chen1, Runchen Miao1, Yanyan Zhou1, Zhixin Wang1, Lingqiang Zhang1, Yong Wan1, Yafeng Dong2, Kai Qu1, Chang Liu1
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
2Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, KS 66160, USA
Chang Liu, e-mail: firstname.lastname@example.org
Kai Qu, e-mail: email@example.com
Keywords: miR-34a, HCC, senescence, telomerase, telomere
Received: October 07, 2014 Accepted: December 11, 2014 Published: January 09, 2015
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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