Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b

Arora, Payal; Kim, Eun‐Ok; Jung, Jin Kyu; Jang, Kyung Lib

doi:10.1016/j.canlet.2007.11.033

Cited by 111 publications

(95 citation statements)

References 33 publications

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“…Although those authors used HCV-infected primary human hepatocytes to substantiate the physiological significance of NS5A as a trigger for EMT by studying only Twist2 mRNA, they clearly stated in the discussion that the molecular mechanism linking NS5A to the regulation of Twist2 remains to be established. Previous studies have shown that the HCV core protein plays a downregulatory role in the E-cadherin promoter, altering the methylation status and resulting in reduced levels of protein expression (4,37). We previously reported the generation of immortalized human hepatocytes (IHH) upon the introduction of the HCV core gene following a brief transition into a fibroblast-like appearance (36).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes

Bose

Meyer

Bisceglie

et al. 2012

J Virol

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Hepatitis C virus (HCV)-mediated liver disease progression may reflect distinct molecular mechanisms for increased hepatocyte growth and hepatic stellate cell activation. In this study, we have observed that primary human hepatocytes, when infected in vitro with cell culture-grown HCV genotype 1a or 2a, display viral RNA and protein expression. Infected hepatocytes displayed a fibroblast-like shape and an extended life span. To understand the changes at the molecular level, we examined epithelial-mesenchymal transition (EMT) markers. Increased mRNA and protein expression levels of vimentin, snail, slug, and twist and a loss of the epithelial cell marker E-cadherin were observed. Snail and twist, when examined separately, were upregulated in chronically HCV-infected liver biopsy specimens, indicating an onset of an active EMT state in the infected liver. An increased expression level of fibroblast-specific protein 1 (FSP-1) in the infected hepatocytes was also evident, indicating a type 2 EMT state. Infected hepatocytes had significantly increased levels of phosphorylated ␤-catenin (Ser 552 ) as an EMT mediator, which translocated into the nucleus and activated Akt. The phosphorylation level of ␤-catenin at Thr 41 /Ser 45 moieties was specifically higher in control than in HCV-infected hepatocytes, implicating an inactivation of ␤-catenin. Together, these results suggested that primary human hepatocytes infected with cell culture-grown HCV display EMT via the activation of the Akt/␤-catenin signaling pathway. This observation may have implications for liver disease progression and therapeutic intervention strategies using inhibitory molecules.

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Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes

Bose

Meyer

Bisceglie

et al. 2012

J Virol

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“…Recently, we and others demonstrated that core downregulates the levels of several tumour suppressors including p16 via promoter hypermethylation (Arora et al, 2008;Lim et al, 2012;Park et al, 2011). For this effect, core upregulates levels of DNMT1 and DNMT3b (Park et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation

Seo

Heo

Jang

2015

Journal of General Virology

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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 H 2 O 2 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 H 2 O 2 induced apoptotic cell death in p53-positive human hepatocytes, but not in p53-negative human hepatocytes. For this effect, H 2 O 2 upregulated levels of p14, increased ubiquitindependent 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 H 2 O 2 to activate the p14-MDM2-p53 pathway. As a consequence, HCV core-expressing cells could overcome p53-mediated apoptosis provoked by H 2 O 2 . Taken together, HCV core could contribute to hepatocellular carcinoma formation by removing deleterious roles of ROS inducing cell death.

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“…HCV also affects in a twofold way expression of E-cadherin, indirectly by modulation of the Wnt/β-catenin pathway and directly with mediation of HCV core protein. C protein diminishes expression of E-cadherin at the transcriptional level, through methylation of CpG islands in the promoter of the CDH1 gene [92,93].…”

Section: Wnt/β-catenin Pathway In Hcv-associated Liver Carcinogenesismentioning

confidence: 99%

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

Rogacki¹,

Kasprzak²,

Stępiński³

2015

pjp

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Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b

Cited by 111 publications

References 33 publications

Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes

Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes

Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

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