miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway

Oncotarget. 2015 Feb 28;6(6):3988-4004. doi: 10.18632/oncotarget.2905.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy*
  • Cell Line, Tumor
  • Cellular Senescence / drug effects
  • Cellular Senescence / genetics
  • Cisplatin / pharmacology
  • Female
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Genetic Vectors / genetics
  • Hep G2 Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Lentivirus / genetics
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy*
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / administration & dosage
  • MicroRNAs / genetics*
  • Middle Aged
  • Prognosis
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Transfection
  • Xenograft Model Antitumor Assays


  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • MIRN34 microRNA, human
  • MYC protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Hydrogen Peroxide
  • Telomerase
  • Cisplatin