Repeated hepatocyte injury promotes hepatic tumorigenesis in hepatitis C virus transgenic mice

Kato, Takanobu; Miyamoto, Michiko; Date, Tomoko; Yasui, Kotaro; Taya, Choji; Yonekawa, Hiromichi; Ohue, Chiharu; Yagi, Shusuke; Seki, Ekihiro; Hirano, Toshio; Fujimoto, Jiro; Shirai, Tomoyuki; Wakita, Takaji

doi:10.1111/j.1349-7006.2003.tb01502.x

Cited by 32 publications

(25 citation statements)

References 43 publications

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“…Ohata et al 74 recently found that steatosis was independently associated with an increased risk of HCC in chronically infected patients, and some support for this clinical finding is found in animal studies. Transgenic mice expressing HCV viral proteins [75][76][77] have an increased risk of developing hepatocellular adenomas and carcinomas. Steatosis occurs in only some of the models as a viral effect, 75,77 and these animals develop spontaneous tumors in the absence of inflammation.…”

Section: Steatosis Obesity and Primary Liver Cancermentioning

confidence: 99%

Steatosis: Co-factor in Other Liver Diseases *

2005

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The prevalence of fatty liver is rising in association with the global increase in obesity and type 2 diabetes. In the past, simple steatosis was regarded as benign, but the presence of another liver disease may provide a synergistic combination of steatosis, cellular adaptation, and oxidative damage that aggravates liver injury. In this review, a major focus is on the role of steatosis as a co-factor in chronic hepatitis C (HCV), where the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. Steatosis, obesity, and associated metabolic factors may also modulate the response to alcohol-and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, and other components of the metabolic syndrome such as hyperinsulinemia and hyperglycemia are likely to have a role. Fibrosis also may be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells. In conclusion, active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis. (HEPATOLOGY 2005;42:5-13.)

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Section: Steatosis Obesity and Primary Liver Cancermentioning

confidence: 99%

Steatosis: Co-factor in Other Liver Diseases *

2005

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“…To mimic chronic hepatic inflammation, mice were intraperitoneally injected with 1 ml/kg CCl 4 solution once a week for 12 weeks. Elevated serum ALT levels return to a normal range 4 days after CCl 4 administration in the liver of C57BL/6 mice (Kato et al, 2003). In addition, single i.p.…”

Section: Discussionmentioning

confidence: 92%

“…To induce hepatic injury, mice were intraperitoneally injected with 1 ml/ kg CCl 4 solution (20 v/v% CCl 4 in corn oil) once a week from week 2. The dose and interval of CCl 4 administration were selected based on a study by Kato et al (2003), as conditions to recover from increased levels of serum alanine aminotransferase (ALT) to basal levels. All mice were sacrificed and a part of the left lateral lobe of the liver was preserved with an ISOGEN kit (Nippon Gene, Tokyo, Japan) and stored at -80ºC until used to isolate total RNA.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…For example, infection by the hepatitis C virus (HCV) is considered a trigger for development of hepatocellular carcinoma, in which the modes of action might involve cell injury and subsequent regenerative cell proliferation by HCV infection (Hayashi et al, 1999;Kato et al, 2003). Alternatively, several cytokines released from inflammatory cells supposedly take part in carcinogenesis (Lu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Enhancing effects of carbon tetrachloride on in vivo mutagenicity in the liver of mice fed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)

et al. 2010

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-Chronic stimulus subsequent to cell injury plays an important role in cancer development, but the precise mechanisms remain unknown partly because appropriate animal models are lacking. In the present study, the effects of hepatotoxicant carbon tetrachloride (CCl 4 ) on in vivo mutagenicity were investigated using gpt delta mice with or without p53. Female B6C3F 1 p53-proficient or -deficient gpt delta mice were given a diet containing 300 ppm of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) for 13 weeks, concurrently with intraperitoneal injection of 1 ml/kg CCl 4 solution once a week. Mutant frequencies of gpt and red/gam in p53-proficient mice fed MeIQx were both significantly elevated by CCl 4 co-treatment. Enhancing effects of CCl 4 treatment were also noted in p53-deficient mice. In the mutation spectra analysis of gpt mutant colonies, G:C to T:A transversions were predominantly observed regardless of CCl 4 injection, and clonal expansion of gpt colonies were increased in the co-treated group as compared with MeIQx alone group. The present data showing no significant changes in mRNA expression levels of CYP1A2 and GSTa4 between MeIQx-treated groups with and without CCl 4 . In the Western blotting analysis, CYP1A2 protein levels were significantly decreased in the co-treated group as compared to MeIQx alone group, and GSTα protein levels were not changed among any groups. It is suggested that the mutant frequency by co-treatment with CCl 4 might result from some factors other than p53 or MeIQx metabolism/excretion. Thus, our data clearly demonstrate that this model could be a powerful tool for identifying the mechanisms underlying combinatorial effects on carcinogenesis.

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“…In addition, these models are applied to study relations between carcinogens (like DEN) and HCV-infection in inducing HCC [75,76] . Furthermore, bitransgenic mouse models have been developed to investigate the effect of a particular gene on HCV-induced hepatocarcinogenesis.…”

Section: Hepatitis C Virus-associated Hccmentioning

confidence: 99%

Mouse models in liver cancer research: A review of current literature

Leenders¹,

Nijkamp²,

Rinkes³

2008

WJG

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Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in East-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used, especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma (HCC), as this is by far the most common type of primary liver cancer, accounting for 70%-85% of cases.

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Repeated hepatocyte injury promotes hepatic tumorigenesis in hepatitis C virus transgenic mice

Abstract: Although hepatitis C virus (HCV) is a well-known causative agent of hepatocellular carcinoma (HCC),

Cited by 32 publications

References 43 publications

Steatosis: Co-factor in Other Liver Diseases *

Steatosis: Co-factor in Other Liver Diseases *

Enhancing effects of carbon tetrachloride on in vivo mutagenicity in the liver of mice fed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)

Mouse models in liver cancer research: A review of current literature

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