Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus

Lerat, Hervé; Honda, Masao; Beard, Michael R.; Loesch, Kim; Sun, Jiaren; Yang, Yan; Okuda, Michiari; Gosert, Rainer; Xiao, Shu‐Yuan; Weinman, Steven A.; Lemon, Stanley M.

doi:10.1053/gast.2002.31001

Cited by 429 publications

(399 citation statements)

References 51 publications

(68 reference statements)

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“…It has been demonstrated that expression of HCV core protein alone is sufficient for the induction of hepatic steatosis and hepatocellular carcinoma in transgenic mice (24,34,35). Furthermore, we demonstrated that nuclear localization and degradation of HCV core protein is regulated by PA28␥-dependent proteolysis (33).…”

Section: Discussionmentioning

confidence: 58%

Intramembrane Proteolysis and Endoplasmic Reticulum Retention of Hepatitis C Virus Core Protein

Okamoto

Moriishi

Miyamura

et al. 2004

J Virol

101

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Section: Discussionmentioning

confidence: 58%

Intramembrane Proteolysis and Endoplasmic Reticulum Retention of Hepatitis C Virus Core Protein

Okamoto

Moriishi

Miyamura

et al. 2004

J Virol

101

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“…These transgenic mice have exhibited two phenotypes: those with and those without hepatic tumors. The tumor phenotype has been reported to occur in transgenic mice for core, 6 the entire region, 9 or coreϩE1ϩE2. 9 However, in different investigations mice transgenic for core, 10 E2, 10 E1ϩE2, 3 and coreϩE1ϩE2, 2 did not exhibit the tumor phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…2 We used the albumin promoter as did Lerat et al 9 The transgenic mice developed by Kawamura et al demonstrated high core expression, 2 whereas those by Lerat et al showed much lower core protein expression, suggesting that levels of core protein expression alone do not explain the HCC phenotype, and that the FVB background may have a protective role in hepatocarcinogenesis. Indeed, saline-treated control animals expressing the core and core-E1-E2 construction on the FVBϫC57Bl/6 background both failed to develop HCC, unless they were exposed to a chemical carcinogen.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis

et al. 2005

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We developed hepatitis C virus (HCV) core-E1-E2 and HCV core transgenic mice on a common genetic background to assess the contribution of HCV structural proteins to hepatocarcinogenesis. Eight-week-old core-E1-E2, core, and nontransgenic mice inbred on the FVB؋C57Bl/6 background were treated with diethylnitrosamine (DEN) and sacrificed at 32 weeks old. Proliferation and apoptosis were assessed by immunohistochemistry. H epatitis C virus (HCV) infects an estimated 170 million people worldwide, and 2.7 million people in the United States harbor active HCV infection. 1 Chronic HCV infection has been independently established as a leading cause of hepatocellular carcinoma (HCC). Unlike hepatitis B virus (HBV), the RNA genome of HCV does not integrate into the host chromosome. HCV-related hepatocarcinogenesis is, therefore, not likely to involve insertional mutagenesis. Rather, it has been hypothesized that HCV produces HCC through the cumulative effects of chronic infection, injury and repair. Whether HCV proteins are directly oncogenic has not been established. Unfortunately, the lack of an appropriate small animal model of HCV has impeded progress in defining the molecular mechanisms of HCV-induced carcinogenesis.We originally developed an HCV transgenic mouse model encoding the core, E1, and E2 structural proteins under the control of the albumin promoter on the FVB background; despite high-level protein expression, this model did not develop hepatic pathology. 2 However, more recently, Moriya et al. developed a transgenic mouse model on the C57Bl/6 background that overexpresses Abbreviations: HCV, hepatitis C virus; DEN, diethylnitrosamine; HCC, hepatocellular carcinoma; AI, apoptotic index; PI, proliferation index. From the

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“…Significantly more nuclei were stained positively for Cre at days 5 and 7 post-induction, and it later disappeared from the nuclei via an as-yet-unidentified mechanism, at days 14 and 21 post-induction. In a previous study, constitutive version of the SL24 transgene resulted in cytoplasmic staining for core and E2 predominantly in pericentral hepatocytes (Lerat et al, 2002). Given the limitations associated commonly with the current constitutive and inducible tg animals, for example, immunotolerance due to premature HCV expression and inflammatory responses against adenoviral vector (Lerat et al, 2002;Sun et al, 2005;Wakita et al, 1998), this novel HCV mouse model offers several obvious advantages, including controlling temporally HCV expression without viral vector-or hydrodynamics-related complications in animals.…”

Section: Tamoxifen Induction Of Hcv Structural Proteins In Tg Micementioning

confidence: 94%

“…Copy numbers of the recombined transgene in the liver were assessed by real-time quantitative PCR on a LightCycler using a QuantiTect SYBR Green PCR kit (Qiagen, Inc., Valencia, CA). A standard curve was generated for the recombined transgene with pALB.HCV-S (Lerat et al, 2002), which was quantified with a Quant-iT PicoGreen dsDNA kit (Qiagen). The amplification reactions were carried out with 5-μl sample aliquots in a 20-μl final volume.…”

Section: Determination Of Cre-mediated Dna Recombinationmentioning

confidence: 99%

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

Tumurbaatar

Sun

Chan

et al. 2007

Journal of Virological Methods

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Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis.

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Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus

Cited by 429 publications

References 51 publications

Intramembrane Proteolysis and Endoplasmic Reticulum Retention of Hepatitis C Virus Core Protein

Intramembrane Proteolysis and Endoplasmic Reticulum Retention of Hepatitis C Virus Core Protein

Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

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