Cell transformation induced by hepatitis C virus NS3 serine protease

Zemel, Romy; Gerechet, S.; Greif, Hagar; Bachmatove, L.; Birk, Yehudith; Golan‐Goldhirsh, Avi; Kunin, Margarita; Berdichevsky, Yevgeny; Benhar, Itai; Tur–Kaspa, Ran

doi:10.1046/j.1365-2893.2001.00283.x

Cited by 79 publications

(71 citation statements)

References 13 publications

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“…The proliferative advantage appears in the immortally normal hepatocyte QSG7701 cells expressing stably HCV NS3 protein, suggesting the potential role of HCV NS3 protein in the promotion of cell growth. The results provide an insight into the mechanisms of how the HCV NS3 protein mediates its oncogenic activity in infected cells and are supported by previous findings (14,16,17). In addition, we also show the HCV NS3-stimulated cell growth is ERK/AP-1 cascade dependent.…”

Section: Discussionsupporting

confidence: 90%

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The effects of hepatitis C virus non-structural protein 3 on cell growth mediated by extracellular signal-related kinase cascades in human hepatocytes in vitro

Feng¹

2010

Int J Mol Med

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Abstract. Hepatitis C virus (HCV) infection has become a severe health problem worldwide. The viral proteins are believed to be among the most important factors that contribute to HCV mediated pathogenesis. Accumulated evidence demonstrating that HCV non-structural protein 3 (NS3) possesses oncogenic potential, and is involved in the regulation of cell proliferation has been documented. In this study, we emphasized the effect of HCV NS3 protein on cell proliferation in the immortally normal hepatocyte QSG7701 cells. The cell line transfected with plasmid expressing NS3 protein showed enhanced cell growth, extracellular signal-related kinase (ERK) activation, DNA binding activities of transcription factors of activator protein 1 (AP-1) and NF-κB, and cyclin D1 overexpression, but without activation of Jun amino-terminal kinase or p38. Pre-treatment of NS3 protein expressing cells with ERK inhibitor, PD98059, blocked the activation of AP-1 and NF-κB, and inhibited cyclin D1 expression and cell proliferation. The results suggest that NS3-mediated cell growth occurs through activation of ERK/AP-1 and NF-κB/cyclin D1 cascades.

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Section: Discussionsupporting

confidence: 90%

“…The oncogenic potential of HCV NS3 protein has been well documented (8,9,14,15). The disturbance of cell proliferation is closely associated with hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

The effects of hepatitis C virus non-structural protein 3 on cell growth mediated by extracellular signal-related kinase cascades in human hepatocytes in vitro

Feng¹

2010

Int J Mol Med

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“…NS3 protein, a 70-kDa nonstructural protein, with NS2-3 and NS5b is required for in vivo infectivity (13,14). The N-terminal 180 aa of NS3 have serine protease activity, while the C-terminal portion encodes the helicase and nucleoside triphosphatase activities (20,21). The helicase activity is required for viral replication, and it is presumed to be involved in unwinding a putative double-stranded replicon intermediate.…”

Section: H Epatitis C Virus (Hcv)mentioning

confidence: 99%

Hepatitis C Virus Core and Nonstructural Protein 3 Proteins Induce Pro- and Anti-inflammatory Cytokines and Inhibit Dendritic Cell Differentiation

Dolganiuc¹,

Kodys²,

Kopasz³

et al. 2003

The Journal of Immunology

230

215

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Antiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-α production in monocytes. Degradation of I-κBα suggested involvement of NF-κB activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-α and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients’ DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.

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“…The immunologically mediated necroinflammatory injury see in hepatitis C infection is some what akin to the situation observed in chronic hepatitis B infection (43). Suggestive evidence of a role for HCV core and NS3 protein in development of hepatocellular carcinoma may indicate that perhaps the gene products of HCV have oncogenic potential (44)(45)(46)(47).…”

Section: Clinicopathology and Virology Of Had-1b Infected Individualsmentioning

confidence: 99%

The Irish paradigm on the natural progression of hepatitis C virus infection: An investigation in a homogeneous patient population infected with HCV 1b (review)

Fanning

2002

Int J Mol Med

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Original citationFanning, L. J. (2002) Abstract. The aetiological agent of chronic hepatitis C is the hepatitis C virus. The hepatitis C virus is spread by parenteral transmission of body fluids, primarily blood or blood products. In 1989, after more than a decade of research, HCV was isolated and characterised. The hepatitis C viral genome is a positive-sense, single-stranded RNA molecule approximately 9.4 kb in length, which encodes a polyprotein of about 3100 amino acids. There are 6 main genotypes of HCV, each further stratified by subtype. In 1994, a cohort of women was identified in Ireland as having been iatrogenically exposed to the hepatitis C virus. The women were all young and exposed as a consequence of the receipt of HCV 1b contaminated anti-D immunoglobulin. The source of the infection was identified as an acutely infected female. As part of a voluntary serological screening programme involving 62,667 people, 704 individuals were identified as seropositive for exposure to the hepatitis C virus; 55.4% were found to be positive for the viral genome 17 years after exposure. Of these women 98% had evidence of inflammation, but suprisingly, a remarkable 49% showed no evidence of fibrosis. Clinicopathology and virological analysis has identified associations between viral load and the histological activity index for inflammation, and, between inflammation and levels of the liver enzyme alanine aminotransferase. Infection at a younger age appears to protect individuals from progression to advanced liver disease. Molecular analyses of host immunogenetic elements shows that particular class II human leukocyte associated antigen alleles are associated with clearance of the hepatitis C virus. Additional class II alleles have been identified that are associated with stable viraemia over an extended period of patient follow-up. Although, investigation of large untreated homogeneous cohorts is likely to become more difficult, as the efficacy of anti-viral therapy improves, further investigation of host and viral factors that influence disease progression will help provide an evidence based approach were realistic expectations regarding patient prognosis can be ascertained.

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Cell transformation induced by hepatitis C virus NS3 serine protease

Cited by 79 publications

References 13 publications

The effects of hepatitis C virus non-structural protein 3 on cell growth mediated by extracellular signal-related kinase cascades in human hepatocytes in vitro

The effects of hepatitis C virus non-structural protein 3 on cell growth mediated by extracellular signal-related kinase cascades in human hepatocytes in vitro

Hepatitis C Virus Core and Nonstructural Protein 3 Proteins Induce Pro- and Anti-inflammatory Cytokines and Inhibit Dendritic Cell Differentiation

The Irish paradigm on the natural progression of hepatitis C virus infection: An investigation in a homogeneous patient population infected with HCV 1b (review)

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