Hepatitis C Virus Causes Uncoupling of Mitotic Checkpoint and Chromosomal Polyploidy through the Rb Pathway

Machida, Keigo; Liu, Jianchang; McNamara, George; Levine, Alexandra; Duan, Lewei; Lai, Michael M. C.

doi:10.1128/jvi.02643-08

Cited by 68 publications

(59 citation statements)

References 60 publications

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“…Unscheduled overexpression of Mad2 can lead to defects in the spindle checkpoint, aneuploidy, and cancer (10). A recent study suggested that HCV core protein can cause transcriptional downregulation of Rb, leading to unscheduled overexpression of Mad2 and aneuploidy (19). Contrary to this report, our data are clear in suggesting that Mad2 protein levels are downregulated by HCV infection (Fig.…”

Section: Discussioncontrasting

confidence: 57%

Hepatitis C Virus Infection Causes Cell Cycle Arrest at the Level of Initiation of Mitosis

Kannan

Hensley

Evers

et al. 2011

J Virol

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Chronic infection with the hepatitis C virus (HCV) is associated with increased risk for hepatocellular carcinoma (HCC). Chronic immune-mediated inflammation is likely to be an important factor in the development of HCV-associated HCC, but direct effects of HCV infection on the host cell cycle may also play a role.Although overexpression studies have revealed multiple interactions between HCV-encoded proteins and host cell cycle regulators and tumor suppressor proteins, the relevance of these observations to HCV-associated liver disease is not clear. We determined the net effect of these interactions on regulation of the cell cycle in the context of virus infection. Flow cytometry of HCV-infected carboxyfluorescein succinimidyl ester-labeled hepatoma cells indicated a slowdown in proliferation that correlated with abundance of viral antigen. A decrease in the proportions of infected cells in G 1 and S phases with an accumulation of cells in G 2 /M phase was observed, compared to mock-infected controls. Dramatic decreases in markers of mitosis, such as phosphohistone H3, in infected cells suggested a block to mitotic entry. In common with findings described in the published literature, we observed caspase 3 activation, suggesting that cell cycle arrest is associated with apoptosis. Differences were observed in patterns of cell cycle disturbance and levels of apoptosis with different strains of HCV. However, the data suggest that cell cycle arrest at the interface of G 2 and mitosis is a common feature of HCV infection.Chronic infection with hepatitis C virus (HCV) is associated with an increased risk for hepatocellular carcinoma (HCC) (8). Typically, cancer only develops after several decades of infection. Although the incidence of newly acquired HCV infections has decreased over the past 20 years, the incidence of HCVassociated HCC is increasing significantly as the infected population ages. Liver cancer associated with chronic HCV infection will, thus, be a significant public health burden for years to come. A greater understanding of the mechanisms by which chronic HCV infection leads to HCC will be critical for the development of improved therapies.HCV has high genetic diversity and has been classified into six major genotypes that differ in their geographical distributions and natural history (33). Globally, infection with genotype 1 is the most common. Currently, only the genotype 1 and 2 HCV genomes have been propagated in cell culture.The mechanisms by which HCV infection leads to HCC are unclear. HCV has an RNA genome with an exclusively cytoplasmic life cycle. Since HCV-associated HCC typically develops in the setting of fibrosis and cirrhosis, HCC development may be driven at least in part by chronic immune-mediated inflammation. However, in vitro studies have revealed multiple interactions between HCV-encoded proteins and host cell cycle regulators and tumor suppressor proteins (24). For example, in vitro studies have shown that three distinct HCV proteins, core (13), NS3 (12), and NS5A (14,20,29), in...

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Section: Discussioncontrasting

confidence: 57%

Hepatitis C Virus Infection Causes Cell Cycle Arrest at the Level of Initiation of Mitosis

Kannan

Hensley

Evers

et al. 2011

J Virol

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“…HBV X (HB X ) protein induces the p38MAPKα pathway leading to pRb phosphorylation and consequently to E2F-1 activation [30]. Contradictory results exist regarding HCV implication in E2F-1/pRb function in hepatocarcinogenesis, although most studies are in favor of E2F-1 upregulation and activation by HCV proteins [31].…”

Section: Discussionmentioning

confidence: 98%

E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma

et al. 2012

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E2F-1 is a transcription factor involved in DNA synthesis and repair, cell proliferation, and apoptosis. Hyposphorylated pRb represses E2F-1 action in early G1 phase, while in late G1, pRb hyperphosphorylation leads to E2F-1 release and activation. In vitro studies have shown that E2F-1 may act either as oncogene or as tumor suppressor gene. We evaluated immunohistochemical expression of E2F-1 protein in chronic viral liver disease and hepatocellular carcinoma (HCC) and correlated this with clinicopathological parameters, cell proliferation, apoptosis, and the expression of E2F-1-regulators, pRb, and phospho-pRb (Ser795). In liver biopsies from 30 patients with chronic viral hepatitis, including 22 with cirrhosis without HCC, and 57 with cirrhosis with HCC, E2F-1 expression was assessed by immunohistochemistry. In chronic hepatitis and cirrhosis, hepatocytes and cholangiocytes demonstrated mild cytoplasmic and/or nuclear membrane E2F-1 immunostaining. In contrast, all HCC (100 %) showed strong nuclear E2F-1 immunostaining, with or without membrane accentuation, while a minority demonstrated additional moderate cytoplasmic immunostaining. Abnormally low pRb and phospho-pRb expression was seen in 70 % and 67.9 % of HCC, respectively. In HCC, nuclear E2F-1 expression was inversely correlated with phospho-pRb expression (p = 0.001) and positively related to tumor apoptotic index (p = 0.025). No significant correlation was found between E2F-1 expression and patient demographics, HCC etiology, tumor grade, pRb, p53 expression, or cell proliferation. In conclusion, we show that the increased expression of E2F-1 protein in human HCC is correlated with enhanced tumor cell apoptosis supporting a pro-apoptotic role of E2F-1 in human HCC.

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“…Massive DNA breakage occurs during the cleavage and packaging of viral concatemeric DNA. In addition, in viral infections there is uncoupling between cell cycle phase and the appearance of cellular proteins characteristic of the particular phase [36].…”

Section: Cell Cycle Arrest In Roseoloviruses Infectionmentioning

confidence: 99%