Malignant transformation of the cultured human normal biliary tract epithelial cells induced by hepatitis C virus core protein

Chen, Ru Fu; Li, Zhi Hua; Liu, Ran Yi; Kong, Xian He; Tang, Qi; Wang, Jie

doi:10.3892/or.17.1.105

Cited by 9 publications

(15 citation statements)

References 19 publications

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“…Core protein interacts with numerous enzymatic systems of the hepatocyte chiefly through activation or repression of proteins such as p53, p21, other transcriptional factors, proto-oncogenes, growth factors, and elements of apoptosis [Kasprzak and Adamek, 2008]. Core protein also facilitates malignant transformation [Shan et al, 2005;Chen et al, 2007], likely through its influence on transcription factor regulation and/or signaling events important for the neoplastic phenotype [Ray and Ray, 2001].…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells

Zhu

Wilson

Gopalakrishna

et al. 2009

Journal of Medical Virology

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Hepatitis C is an oncogenic virus although the mechanisms responsible for this behavior are not clear. We studied the effects of hepatitis C virus (HCV) core protein expression on Telomerase, an enzyme closely associated with cellular immortalization and neoplasia. The aim of this study was to investigate the effects of HCV core protein on the regulation of Telomerase activity in human hepatoma cells. Regulation and expression of human Telomerase reverse transcriptase (TERT) was compared in Huh7 cells stably transfected with HCV core protein or cells expressing vector alone. Telomerase activity was measured using Quantitative Telomerase Detection (QTD) and telomere length was measured by fluorescence in situ hybridization (FISH). Transient transfection and luciferase assay were used to evaluate TERT promoter activity. Telomerase activity was increased twofold in Huh7 cells expressing HCV core protein compared to controls (P < 0.01). This was accompanied by a 1.4-fold increase of TERT mRNA and 1.9-fold increase in TERT protein (P < 0.01 in either case). Cellular fractionation and immunocytochemical studies showed increased localization of TERT in the nucleus of core-expressing cells as compared to controls. FISH assay confirmed that telomeres of HCV core-expressing Huh7 cells were relatively longer than those of control cells (0.22 + 0.05 vs. 0.12 + 0.03, P < 0.01). TERT promoter activity was enhanced about 30% in HCV core-expressing Huh7 cells compared to control cells (P < 0.02). HCV core protein is associated with increased Telomerase activity in hepatoma cells. These findings suggest that enhancement of Telomerase activity by HCV core protein may contribute to the oncogenicity of HCV.

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Section: Introductionmentioning

confidence: 99%

Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells

Zhu

Wilson

Gopalakrishna

et al. 2009

Journal of Medical Virology

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“…The incidence of hilar cholangiocarcinoma grows higher worldwide and the number of hilar cholangiocarcinoma patients with hepatitis C virus (HCV) infection is continuously increasing [1,2]. The core protein of HCV (HCVc) is a structural protein encoded by the most conservative region of HCV genome, and is considered to play an important role in tumor genesis [3,4]. In our previous research, we found that the transfection of HCVc into normal human biliary epithelial cell line led to the malignant transformation [5].…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus core upregulates the methylation status of the RASSF1A promoter through regulation of SMYD3 in hilar cholangiocarcinoma cells

Guo¹,

Chen²,

Li³

et al. 2011

ABBS

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Increasing evidence has been accumulated indicating the important role of epigenetic regulation in tumor genesis. Previously, we observed that the transfection of hepatitis C virus core (HCVc) protein led to malignant transformation in normal biliary cells, and that tumor suppressor gene RASSF1A was downregulated in many hilar cholangiocarcinoma patients by hypermethylation in the promoter region. In the present study, we found SET and MYND domain-containing protein 3 (SMYD3), a novel histone methyltransferase, was overexpressed in cholangiocarcinoma patients especially in those with HCV infection. Transfection of HCVc into hilar cholangiocarcinoma cell lines QBC939 and FRH0201 could upregulate the expression of SMYD3 and promote cell growth, which was consistent with the results of our clinical research. This phenomenon indicated that SMYD3 was related to the epigenetic regulation of cholangiocarcinoma genesis with HCV infection. Overexpression of SMYD3 could inhibit RASSF1A expression, whereas inhibition of SMYD3 by siRNA improved its expression. Methylationspecific polymerase chain reaction (MS-PCR) results showed the methylation status of RASSF1A promoter was regulated by SMYD3. In conclusion, HCVc could upregulate the methylation status of the RASSF1A promoter through regulation of SMYD3, and histone methylation may affect the DNA methylation of downstream gene by an unknown mechanism.

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“…Damage to the bile duct is a histological characteristic of chronic HCV infection, which has been found to be a risk factor for intrahepatic cholangiocarcinoma 16 . The HCV core protein could also promote the malignant transformation of human biliary epithelial cells 17 . Loriot et al .…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Infection Increases Risk of Gallstone Disease in Elderly Chinese Patients with Chronic Liver Disease

Gao

2018

Sci Rep

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We investigated possible links between the etiology of liver disease and gallstone risk in Chinese patients with chronic liver disease (CLD). We compared the outcomes of 267 Chinese CLD patients with gallstones and those of a control group of 1,015 CLD patients without gallstones. Logistic regression analyses adjusting for demographic features and other gallstone risk factors revealed that liver cirrhosis increased the risk of gallstone development twofold [adjusted odds ratio (AOR); 95% confidence interval (95% CI): 2.343 (1.710–3.211)]. HCV infection increased gallstone risk 1–2-fold [AOR; 95% CI: 1.582 (1.066–2.347)] higher than did HBV infection. Multivariate analyses of the risk of developing gallstones in patients with liver cirrhosis after an HCV or HBV infection yielded an estimated AOR (95% CI) of 1.601 (1.063–2.413) in patients with an HCV infection. In elderly patients with CLD (≥60 years of age), gallstone risk also increased significantly after an HCV infection [AOR (95% CI): 2.394 (1.066–5.375)]. HCV infection, older age, and liver cirrhosis significantly correlate with an increased risk of gallstone development in Chinese patients with CLD. HCV infection further increases this risk in both patients with liver cirrhosis and in elderly CLD patients (≥60 years of age).

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Malignant transformation of the cultured human normal biliary tract epithelial cells induced by hepatitis C virus core protein

Cited by 9 publications

References 19 publications

Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells

Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells

Hepatitis C virus core upregulates the methylation status of the RASSF1A promoter through regulation of SMYD3 in hilar cholangiocarcinoma cells

Hepatitis C Virus Infection Increases Risk of Gallstone Disease in Elderly Chinese Patients with Chronic Liver Disease

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