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.
Highlights
Hepatocellular carcinoma (HCC), the second leading cause of cancer-related deaths worldwide, is rarely detected early and is usually fatal within the months after diagnosis [1]
Our data showed that miR-34a, miR-34b and miR-34c were underexpressed in more than half HCC samples compared with the adjacent tissues, suggesting that down-regulation of miR-34 famlily might be involved in the hepatic carcinogenesis (P < 0.05, Figure 1A–1B)
This relationship was verified by the multivariate Cox regression analysis, which demonstrates that both miR-34a and miR-34b could be independent prognostic factors for the overall survival and recurrence in HCC patients underwent surgical resection (Table 1)
Summary
Hepatocellular carcinoma (HCC), the second leading cause of cancer-related deaths worldwide, is rarely detected early and is usually fatal within the months after diagnosis [1]. Recent studies indicate that cancer cell senescence, a state of irreversible growth arrest, is a potential mechanism of HCC regression following chemotherapy [3]. Our previous results demonstrated that cellular senescence would contribute to the chemotherapy response among HCC patients [5, 6]. Cellular senescence can be triggered by different mechanisms including telomere shortening, epigenetic derepression of INK4a/ARF locus, and DNA damage [7]. Hepatocytes exhibiting telomere dysfunction would undergo senescence, as significant barriers to cancer formation. It was reported that hepatocyte telomere shortening was accelerated in patients with chronic liver disease, accompanied with increased number of β-galactosidase (SA-β-Gal)-positive cells, a marker of senescence [8]. Telomere and telomerase-based therapy to induce cellular senescence in cancer was supposed to be a promising anti-tumor method [12]
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