1887

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Volume 96, Issue 4

Hepatitis C virus core protein overcomes HO-induced apoptosis by downregulating p14 expression via DNA methylation Free

Abstract

Infection with hepatitis C virus (HCV) is characterized by systemic oxidative stress that is caused by either viral core protein or chronic inflammation. It is well recognized that reactive oxygen species (ROS) such as HO can induce apoptotic cell death and can therefore function as anti-tumorigenic species. However, the detailed mechanisms by which ROS induce apoptotic cell death and HCV copes with the oxidative conditions are largely unknown. In the present study, we found that HO induced apoptotic cell death in p53-positive human hepatocytes, but not in p53-negative human hepatocytes. For this effect, HO upregulated levels of p14, increased ubiquitin-dependent degradation of mouse double minute 2 (MDM2), and reduced the interaction between MDM2 and p53 to prevent p53 degradation, resulting in accumulation of p53 and subsequent activation of p53-dependent apoptotic pathways. Interestingly, HCV core repressed p14 expression via promoter hypermethylation to abolish the potential of HO to activate the p14–MDM2–p53 pathway. As a consequence, HCV core-expressing cells could overcome p53-mediated apoptosis provoked by HO. Taken together, HCV core could contribute to hepatocellular carcinoma formation by removing deleterious roles of ROS inducing cell death.

  • Received:
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© 2015 The Authors
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2015-04-01
2024-04-27
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References

  1. Achanta G., Huang P. 2004; Role of p53 in sensing oxidative DNA damage in response to reactive oxygen species-generating agents. Cancer Res 64:6233–6239 [View Article][PubMed]
     [Google Scholar]
  2. Arora P., Kim E. O., Jung J. K., Jang K. L. 2008; Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Lett 261:244–252 [View Article][PubMed]
     [Google Scholar]
  3. Campisi J. 2005; Suppressing cancer: the importance of being senescent. Science 309:886–887 [View Article][PubMed]
     [Google Scholar]
  4. Caselmann W. H., Alt M. 1996; Hepatitis C virus infection as a major risk factor for hepatocellular carcinoma. J Hepatol 24:Suppl61–66[PubMed]
     [Google Scholar]
  5. Choi J., Ou J. H. 2006; Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol 290:G847–G851 [View Article][PubMed]
     [Google Scholar]
  6. Enoch T., Norbury C. 1995; Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem Sci 20:426–430 [View Article][PubMed]
     [Google Scholar]
  7. Esteller M., Cordon-Cardo C., Corn P. G., Meltzer S. J., Pohar K. S., Watkins D. N., Capella G., Peinado M. A., Matias-Guiu X. other authors 2001; p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Cancer Res 61:2816–2821[PubMed]
     [Google Scholar]
  8. Farinati F., Cardin R., Bortolami M., Burra P., Russo F. P., Rugge M., Guido M., Sergio A., Naccarato R. 2007; Hepatitis C virus: from oxygen free radicals to hepatocellular carcinoma. J Viral Hepat 14:821–829[PubMed]
     [Google Scholar]
  9. Gallagher S. J., Kefford R. F., Rizos H. 2006; The ARF tumour suppressor. Int J Biochem Cell Biol 38:1637–1641 [View Article][PubMed]
     [Google Scholar]
  10. Gao C. F., Ren S., Zhang L., Nakajima T., Ichinose S., Hara T., Koike K., Tsuchida N. 2001; Caspase-dependent cytosolic release of cytochrome c and membrane translocation of Bax in p53-induced apoptosis. Exp Cell Res 265:145–151 [View Article][PubMed]
     [Google Scholar]
  11. Gil J., Peters G. 2006; Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7:667–677 [View Article][PubMed]
     [Google Scholar]
  12. González-Gallego J., García-Mediavilla M. V., Sánchez-Campos S. 2011; Hepatitis C virus, oxidative stress and steatosis: current status and perspectives. Curr Mol Med 11:373–390 [View Article][PubMed]
     [Google Scholar]
  13. Haupt Y., Maya R., Kazaz A., Oren M. 1997; Mdm2 promotes the rapid degradation of p53. Nature 387:296–299 [View Article][PubMed]
     [Google Scholar]
  14. Herman J. G., Graff J. R., Myöhänen S., Nelkin B. D., Baylin S. B. 1996; Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826 [View Article][PubMed]
     [Google Scholar]
  15. Kao C. F., Chen S. Y., Chen J. Y., Wu Lee Y. H. 2004; Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein. Oncogene 23:2472–2483 [View Article][PubMed]
     [Google Scholar]
  16. Kato N., Yoshida H., Ono-Nita S. K., Kato J., Goto T., Otsuka M., Lan K., Matsushima K., Shiratori Y., Omata M. 2000; Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer. Hepatology 32:405–412 [View Article][PubMed]
     [Google Scholar]
  17. Kato T., Date T., Miyamoto M., Furusaka A., Tokushige K., Mizokami M., Wakita T. 2003; Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. Gastroenterology 125:1808–1817 [View Article][PubMed]
     [Google Scholar]
  18. Khosravi R., Maya R., Gottlieb T., Oren M., Shiloh Y., Shkedy D. 1999; Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci U S A 96:14973–14977 [View Article][PubMed]
     [Google Scholar]
  19. Koike K. 2007; Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol Hepatol 22:Suppl 1S108–S111 [View Article][PubMed]
     [Google Scholar]
  20. Korenaga M., Wang T., Li Y., Showalter L. A., Chan T., Sun J., Weinman S. A. 2005; Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem 280:37481–37488 [View Article][PubMed]
     [Google Scholar]
  21. Kwun H. J., Jang K. L. 2003; Dual effects of hepatitis C virus Core protein on the transcription of cyclin-dependent kinase inhibitor p21 gene. J Viral Hepat 10:249–255 [View Article][PubMed]
     [Google Scholar]
  22. Kwun H. J., Jang K. L. 2004; Natural variants of hepatitis B virus X protein have differential effects on the expression of cyclin-dependent kinase inhibitor p21 gene. Nucleic Acids Res 32:2202–2213 [View Article][PubMed]
     [Google Scholar]
  23. Lee H., Seo S. Y., Tiwari I., Jang K. L. 2012; Epstein–Barr virus latent membrane protein 1 overcomes all-trans retinoic acid-induced apoptosis by inhibiting retinoic acid receptor-β2 expression. Biochem Biophys Res Commun 423:313–318 [View Article][PubMed]
     [Google Scholar]
  24. Li Y., Raffo A. J., Drew L., Mao Y., Tran A., Petrylak D. P., Fine R. L. 2003; Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143. Cancer Res 63:1527–1533[PubMed]
     [Google Scholar]
  25. Liang T. J., Heller T. 2004; Pathogenesis of hepatitis C-associated hepatocellular carcinoma. Gastroenterology 127:Suppl 1S62–S71 [View Article][PubMed]
     [Google Scholar]
  26. Lim J. S., Park S. H., Jang K. L. 2012; Hepatitis C virus Core protein overcomes stress-induced premature senescence by down-regulating p16 expression via DNA methylation. Cancer Lett 321:154–161 [View Article][PubMed]
     [Google Scholar]
  27. Lu W., Lo S. Y., Chen M., Wu K., Fung Y. K., Ou J. H. 1999; Activation of p53 tumor suppressor by hepatitis C virus core protein. Virology 264:134–141 [View Article][PubMed]
     [Google Scholar]
  28. Maheshwari A., Misro M. M., Aggarwal A., Sharma R. K., Nandan D. 2009; Pathways involved in testicular germ cell apoptosis induced by H2O2 in vitro . FEBS J 276:870–881 [View Article][PubMed]
     [Google Scholar]
  29. Matés J. M., Segura J. A., Alonso F. J., Márquez J. 2008; Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis. Arch Toxicol 82:273–299 [View Article][PubMed]
     [Google Scholar]
  30. Michael D., Oren M. 2003; The p53–Mdm2 module and the ubiquitin system. Semin Cancer Biol 13:49–58 [View Article][PubMed]
     [Google Scholar]
  31. Moriya K., Fujie H., Shintani Y., Yotsuyanagi H., Tsutsumi T., Ishibashi K., Matsuura Y., Kimura S., Miyamura T., Koike K. 1998; The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4:1065–1067 [View Article][PubMed]
     [Google Scholar]
  32. Muriel P. 2009; Role of free radicals in liver diseases. Hepatol Int 3:526–536 [View Article][PubMed]
     [Google Scholar]
  33. Okuda M., Li K., Beard M. R., Showalter L. A., Scholle F., Lemon S. M., Weinman S. A. 2002; Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122:366–375 [View Article][PubMed]
     [Google Scholar]
  34. Otsuka M., Kato N., Lan K., Yoshida H., Kato J., Goto T., Shiratori Y., Omata M. 2000; Hepatitis C virus core protein enhances p53 function through augmentation of DNA binding affinity and transcriptional ability. J Biol Chem 275:34122–34130 [View Article][PubMed]
     [Google Scholar]
  35. Ott M., Gogvadze V., Orrenius S., Zhivotovsky B. 2007; Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922 [View Article][PubMed]
     [Google Scholar]
  36. Park S. H., Lim J. S., Lim S. Y., Tiwari I., Jang K. L. 2011; Hepatitis C virus Core protein stimulates cell growth by down-regulating p16 expression via DNA methylation. Cancer Lett 310:61–68[PubMed] [CrossRef]
     [Google Scholar]
  37. Peng C. Y., Chen T. C., Hung S. P., Chen M. F., Yeh C. T., Tsai S. L., Chu C. M., Liaw Y. F. 2002; Genetic alterations of INK4alpha/ARF locus and p53 in human hepatocellular carcinoma. Anticancer Res 22:2B1265–1271[PubMed]
     [Google Scholar]
  38. Pomerantz J., Schreiber-Agus N., Liégeois N. J., Silverman A., Alland L., Chin L., Potes J., Chen K., Orlow I. other authors 1998; The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 92:713–723 [View Article][PubMed]
     [Google Scholar]
  39. Ray R. B., Lagging L. M., Meyer K., Ray R. 1996; Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J Virol 70:4438–4443[PubMed]
     [Google Scholar]
  40. Robertson K. D., Jones P. A. 1999; Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus. Oncogene 18:3810–3820 [View Article][PubMed]
     [Google Scholar]
  41. Suzuki T., Aizaki H., Murakami K., Shoji I., Wakita T. 2007; Molecular biology of hepatitis C virus. J Gastroenterol 42:411–423 [View Article][PubMed]
     [Google Scholar]
  42. Takeuchi T., Katsume A., Tanaka T., Abe A., Inoue K., Tsukiyama-Kohara K., Kawaguchi R., Tanaka S., Kohara M. 1999; Real-time detection system for quantification of hepatitis C virus genome. Gastroenterology 116:636–642 [View Article][PubMed]
     [Google Scholar]
  43. Tamura H., Ohtsuru A., Kamohara Y., Fujioka H., Yanaga K., Kanematsu T., Yamashita S. 2003; Bax cleavage implicates caspase-dependent H2O2-induced apoptosis of hepatocytes. Int J Mol Med 11:369–374[PubMed]
     [Google Scholar]
  44. Wu Y., Wang D., Wang X., Wang Y., Ren F., Chang D., Chang Z., Jia B. 2011; Caspase 3 is activated through caspase 8 instead of caspase 9 during H2O2-induced apoptosis in HeLa cells. Cell Physiol Biochem 27:539–546 [View Article][PubMed]
     [Google Scholar]
  45. Zhang Y., Xiong Y. 2001; Control of p53 ubiquitination and nuclear export by MDM2 and ARF. Cell Growth Differ 12:175–186[PubMed]
     [Google Scholar]
  46. Zhang Y., Xiong Y., Yarbrough W. G. 1998; ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725–734 [View Article][PubMed]
     [Google Scholar]
  47. Zhong J., Gastaminza P., Cheng G., Kapadia S., Kato T., Burton D. R., Wieland S. F., Uprichard S. L., Wakita T., Chisari F. V. 2005; Robust hepatitis C virus infection in vitro . Proc Natl Acad Sci U S A 102:9294–9299 [View Article][PubMed]
     [Google Scholar]
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Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation
J. Gen. Virol. 96, 822 (2015); https://doi.org/10.1099/vir.0.000032
/content/journal/jgv/10.1099/vir.0.000032
/content/journal/jgv/10.1099/vir.0.000032
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