MiR-34a Induces Cellular Senescence Via Modulation of Telomerase Activity in Human Hepatocellular Carcinoma by Targeting FoxM1/c-Myc Pathway

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Feb 18

PMID 25686834

Citations 62

Authors

Xinsen Xu

Wei Chen

Runchen Miao

Yanyan Zhou

Zhixin Wang

Lingqiang Zhang

Yong Wan

Yafeng Dong

Kai Qu

Chang Liu

Affiliations

Soon will be listed here.

Abstract

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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References

Menard L, Taras D, Grigoletto A, Haurie V, Nicou A, Dugot-Senant N . In vivo silencing of Reptin blocks the progression of human hepatocellular carcinoma in xenografts and is associated with replicative senescence. J Hepatol. 2010; 52(5):681-9. DOI: 10.1016/j.jhep.2009.12.029. View

Christoffersen N, Shalgi R, Frankel L, Leucci E, Lees M, Klausen M . p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ. 2009; 17(2):236-45. DOI: 10.1038/cdd.2009.109. View

Sukata T, Sumida K, Kushida M, Ogata K, Miyata K, Yabushita S . Circulating microRNAs, possible indicators of progress of rat hepatocarcinogenesis from early stages. Toxicol Lett. 2010; 200(1-2):46-52. DOI: 10.1016/j.toxlet.2010.10.013. View

Bai X, Ma Y, Ding R, Fu B, Shi S, Chen X . miR-335 and miR-34a Promote renal senescence by suppressing mitochondrial antioxidative enzymes. J Am Soc Nephrol. 2011; 22(7):1252-61. PMC: 3137573. DOI: 10.1681/ASN.2010040367. View

Chen F, Hu S . Effect of microRNA-34a in cell cycle, differentiation, and apoptosis: a review. J Biochem Mol Toxicol. 2011; 26(2):79-86. DOI: 10.1002/jbt.20412. View

Daniel M, Peek G, Tollefsbol T . Regulation of the human catalytic subunit of telomerase (hTERT). Gene. 2012; 498(2):135-46. PMC: 3312932. DOI: 10.1016/j.gene.2012.01.095. View

Maluccio M, Covey A . Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 2012; 62(6):394-9. DOI: 10.3322/caac.21161. View

Williams S . No end in sight for telomerase-targeted cancer drugs. Nat Med. 2013; 19(1):6. DOI: 10.1038/nm0113-6. View

Qu K, Xu X, Liu C, Wu Q, Wei J, Meng F . Negative regulation of transcription factor FoxM1 by p53 enhances oxaliplatin-induced senescence in hepatocellular carcinoma. Cancer Lett. 2012; 331(1):105-14. DOI: 10.1016/j.canlet.2012.12.008. View

10.

Zhang Y, Sturgis E, Dahlstrom K, Wen J, Liu H, Wei Q . Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma. Cancer Res. 2013; 73(19):5996-6003. PMC: 3790860. DOI: 10.1158/0008-5472.CAN-13-0881. View

11.

Siegel R, Ma J, Zou Z, Jemal A . Cancer statistics, 2014. CA Cancer J Clin. 2014; 64(1):9-29. DOI: 10.3322/caac.21208. View

12.

Chen L, Lu M, Zhang D, Hao N, Fan Y, Wu Y . miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase. Cell Death Dis. 2014; 5:e1034. PMC: 4040688. DOI: 10.1038/cddis.2013.553. View

13.

Jin K, Xiang Y, Tang J, Wu G, Li J, Xiao H . miR-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells. Tumour Biol. 2013; 35(2):1503-10. DOI: 10.1007/s13277-013-1207-z. View

14.

Qu K, Lin T, Wang Z, Liu S, Chang H, Xu X . Reactive oxygen species generation is essential for cisplatin-induced accelerated senescence in hepatocellular carcinoma. Front Med. 2014; 8(2):227-35. DOI: 10.1007/s11684-014-0327-1. View

15.

Te Poele R, Okorokov A, Jardine L, Cummings J, Joel S . DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 2002; 62(6):1876-83. View

16.

Wiemann S, Satyanarayana A, Tsahuridu M, Tillmann H, Zender L, Klempnauer J . Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 2002; 16(9):935-42. DOI: 10.1096/fj.01-0977com. View

17.

Fernandez P, Frank S, Wang L, Schroeder M, Liu S, Greene J . Genomic targets of the human c-Myc protein. Genes Dev. 2003; 17(9):1115-29. PMC: 196049. DOI: 10.1101/gad.1067003. View

18.

Sharpless N, DePinho R . Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004; 113(2):160-8. PMC: 311439. DOI: 10.1172/JCI20761. View

19.

Bartel D . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116(2):281-97. DOI: 10.1016/s0092-8674(04)00045-5. View

20.

Nakamura T, Morin G, Chapman K, Weinrich S, Andrews W, Lingner J . Telomerase catalytic subunit homologs from fission yeast and human. Science. 1997; 277(5328):955-9. DOI: 10.1126/science.277.5328.955. View