HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice†

Kawamura, Hiroki; Govindarajan, Sugantha; Aswad, Fred; Machida, Keigo; Lai, Michael M. C.; Sung, Vicky M.-H.; Dennert, Günther

doi:10.1002/hep.21360

Cited by 28 publications

(22 citation statements)

References 29 publications

(65 reference statements)

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“…Investigations of HCV activation of STAT3 have been controversial. It has been reported that HCV core protein and NS5A protein activate STAT3 in hepatic cells (Gong et al, 2001;Kawamura et al, 2006), whereas other studies show that HCV replication in Huh7 cells inhibit STAT3 signaling (Larrea et al, 2006). Thus, whether HCV contributes to STAT3 activation in these HCV cirrhotic livers requires further study.…”

Section: Discussionmentioning

confidence: 93%

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Horiguchi¹,

Ishac²,

Gao³

2007

Alcohol

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Liver regeneration is suppressed in alcoholic patients; however, the underlying mechanisms are not fully understood. We examined liver regeneration and STAT3 activation (an important signal for liver regeneration) in cirrhotic livers from alcoholics, HCV infection, and alcoholic plus HCV infection. Liver regeneration and STAT3 activation were determined by immunohistochemistry analysis of Ki67 and STAT3 phosphorylation, respectively, in 20 alcoholic cirrhosis, 13 HCV cirrhosis, 13 alcoholic+HCV cirrhosis. Alcoholic or alcoholic plus HCV cirrhotic livers had significantly lower Ki67 + and pSTAT3 + hepatocytes and bile duct cells than HCV cirrhotic livers. The pSTAT3 positive staining did not correlate with liver injury (elevation of serum levels of aspartate transaminase (ALT) and alkaline phosphatase (ALP) but correlated positively with cell proliferation (Ki67 positive staining). In conclusion: Liver regeneration is suppressed in alcoholic cirrhotic livers, which may be partly due to decreased STAT3 activation.

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Section: Discussionmentioning

confidence: 93%

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Horiguchi¹,

Ishac²,

Gao³

2007

Alcohol

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“…Finally, it has been reported in a variety of models that liver disease progression is controlled tightly by the mutual antagonism of IFN-␥/STAT1 and IL-6/STAT3, which negatively regulate one another (19,23,34,38). Such mutual antagonism and regulation are likely involved in the allogeneic transplantation model.…”

Section: Discussionmentioning

confidence: 94%

Activation of innate immunity (NK/IFN-γ) in rat allogeneic liver transplantation: contribution to liver injury and suppression of hepatocyte proliferation

Shen

Zheng

Park³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liver transplantation is presently the only curative treatment for patients with end-stage liver disease. However, the mechanisms underlying liver injury and hepatocyte proliferation posttransplantation remain obscure. In this investigation, liver injury and hepatocyte proliferation in syngeneic and allogeneic animal models were compared. Male Lewis and Dark Agouti (DA) rats were subjected to orthotopic liver transplantation (OLT). Rat OLT was performed in syngeneic (Lewis-Lewis) and allogeneic (Lewis-DA or DA-Lewis) animal models. Allogeneic liver grafts exhibited greater injury and cellular apoptosis than syngeneic grafts but less hepatocyte proliferation after OLT. Expression of IFN-gamma mRNA and activation of the downstream signal transducer and activator of transcription 1 (STAT1) and genes (interferon regulatory factor-1 and cyclin-dependent kinase inhibitor p21(CDKN1A)) were also greater in the allogeneic grafts compared with the syngeneic grafts. In contrast, STAT3 activation was lower in the allogeneic grafts. Furthermore, in the allogeneic grafts, depletion of natural killer (NK) cells decreased IFN-gamma/STAT1 activation but enhanced hepatocyte proliferation. These findings suggest that, compared with syngeneic transplantation, innate immunity (NK/IFN-gamma) is activated after allogeneic transplantation, which likely contributes to liver injury and inhibits hepatocyte proliferation.

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“…62,63 The HBV X protein, required for viral replication and correlated with the hepatocarcinogenesis of individuals chronically infected with HBV, modulates RNA polymerase I-dependent rRNA transcription by enhancing the rRNA promoter activity, 62 and activates specific RNA polymerase III-dependent promoters. 63 The HCV core protein, implicated in the control of cell growth and proliferation, 64,65 enhances the recruitment of UBF and RNA polymerase I to the rRNA promoter and cooperates in the activation of RNA polymerase IIIdependent transcription. 66 According to these findings, it has been suggested that the increased ribosome production induced by these viral proteins may play an important role during tumorigenesis by sustaining an enhanced rate of cell proliferation.…”

Section: Nucleolar Functional Up-regulation As a Risk Factor In Develmentioning

confidence: 99%

Nucleolus, Ribosomes, and Cancer

Montanaro

Trerè

Derenzini

2008

The American Journal of Pathology

405

346

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The complex aspects linking the nucleolus and ribosome biogenesis to cancer are reviewed here. The available evidence indicates that the morphological and functional changes in the nucleolus, widely observed in cancer tissues, are a consequence of both the increased demand for ribosome biogenesis, which characterizes proliferating cells, and the changes in the mechanisms controlling cell proliferation. In fact, the loss or functional changes in the two major tumor suppressor proteins pRB and p53 cause an up-regulation of ribosome biogenesis in cancer tissues. In this context, the association in human carcinomas of nucleolar hypertrophy with bad prognoses is worthy of note. Further, an increasing amount of data coming from studies on both hepatitis virus-induced chronic liver diseases and a subset of rare inherited disorders, including X-linked dyskeratosis congenita, suggests an active role of the nucleolus in tumorigenesis. Both an up-regulation of ribosome production and changes in the ribosome structure might causally contribute to neoplastic transformation, by affecting the balance of protein translation, thus altering the synthesis of proteins that play an important role in the genesis of cancer. (Am J Pathol

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HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice†

Cited by 28 publications

References 29 publications

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Activation of innate immunity (NK/IFN-γ) in rat allogeneic liver transplantation: contribution to liver injury and suppression of hepatocyte proliferation

Nucleolus, Ribosomes, and Cancer

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