Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein

Yu, Dae‐Yeul; Moon, Hyung–Bae; Son, Jin-Kyong; Jeong, Sangkyun; Yu, Seong-Lan; Yoon, Heesik; Han, Yong‐Mahn; Lee, Chul-Sang; Park, Jungsun; Lee, Chul‐Ho; Hyun, Byung-Hwa; Murakami, Seishi; Lee, Kyung-Kwang

doi:10.1016/s0168-8278(99)80172-x

Cited by 230 publications

(233 citation statements)

References 29 publications

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“…We used the HBx homozygote TG mice at different ages and age-matched C57BL/6 WT mice (Yu et al, 1999;Yoo et al, 2003). The experimental protocol was approved by the Committee for Care and Use of Laboratory Animals at Seoul National University, according to the Guide for Animal Experiments edited by Korean Academy for Medical Sciences.…”

Section: Animals Tumor Samples and Immunohistochemistrymentioning

confidence: 99%

“…Forced expression of HBx protein enhanced the survival and proliferative potential of liver cells, whereas knockdown of HBx gene reduces the tumorigenicity of HCC cells (Yun et al, 2002;Chan and Ng, 2006). Further, exogenous HBx expression has been linked to the induction of liver tumors in transgenic (TG) mice (Kim et al, 1991;Yu et al, 1999;Wu et al, 2006). Hepatocellular carcinoma cells frequently show early invasion into blood vessels as well as formation of intrahepatic metastases (Kondo and Wada, 1991).…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

et al. 2008

Oncogene

143

129

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Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1a (HIF-1a) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1a, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1a. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1a. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBxtransgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1a, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

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Section: Animals Tumor Samples and Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

et al. 2008

Oncogene

143

129

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“…The plasmid pHEX is a previously reported vector prepared by us that expresses the HBX gene under authentic promoter control (Yu et al, 1999). Injectable DNA containing HBV enhancer, NS4B, and SV40 poly A sequences was obtained by the removal of phagemid sequences from pUC118 at Kpn I/Hind III sites.…”

Section: Generation and Identification Of Transgenic Micementioning

confidence: 99%

“…Injectable DNA containing HBV enhancer, NS4B, and SV40 poly A sequences was obtained by the removal of phagemid sequences from pUC118 at Kpn I/Hind III sites. DNA was microinjected into fertilized mouse eggs of hybrid BCF1 (C57BL/6J♀ x CBA/J), and the injected eggs were transferred into pseudopregnant recipients as previously described (Yu et al, 1999). Potential founders were analyzed by polymerase chain reaction (PCR) and Southern blot analysis of tail DNA.…”

Section: Generation and Identification Of Transgenic Micementioning

confidence: 99%

“…The histopathological diagnoses were based on the criteria described by Frith and Ward (Frith et al, 1979). The immunohistochemical studies were performed on formalin-fixed, paraffinembedded, 4 m-thick tissue sections using the streptavidin-biotin peroxidase complex method, as previously described (Yu et al, 1999). The primary antibody used was the mouse monoclonal anti-NS4B antibody (Advanced Immunochemical Inc.).…”

Section: Histopathological Diagnoses and Immunohistochemical Stainingmentioning

confidence: 99%

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Expression of hepatitis C virus nonstructural 4B in transgenic mice

Wang

Moon²,

Kim³

et al. 2006

Exp Mol Med

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Hepatitis C virus (HCV) is a pathogen that is of great medical significance in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Although the HCV proteins have been intensively investigated over the past decade, the biochemical functions of the NS4B protein are still largely unknown. To investigate NS4B as a potential causative agent of liver disease, transgenic mice expressing the NS4B protein in liver tissue were produced. The transgenic animals were phenotypically similar to their normal littermates for up to 18 months of age. Our results suggest that the HCV NS4B protein is not directly cytopathic or oncogenic in our transgenic mice model.

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Modeling Human Liver Cancer Heterogeneity: Virally Induced Transgenic Models and Mouse Genetic Models of Chronic Liver Inflammation

Ringelhan

Reisinger²,

Yuan³

et al. 2014

CP Pharmacology

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In addition to being the most common primary liver cancer, hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in humans. Treatment options are limited for this chemoresistant cancer, with liver transplantation and surgical intervention in early stages being the most successful treatments. Drug development over the past 15 years has focused on generating mouse models that mimic the human pathology for HCC. This has enabled the laboratory testing of potentially new human therapeutics. Described in this unit are the classification of HCC and an overview of hepatitis virus-related transgenic and genetically engineered mouse models (GEMMs) that are employed for elucidating the mechanism(s) responsible for the development of HCC, with particular emphasis on genetic, dietary, and environmental factors.

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Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein

Cited by 230 publications

References 29 publications

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

Expression of hepatitis C virus nonstructural 4B in transgenic mice

Modeling Human Liver Cancer Heterogeneity: Virally Induced Transgenic Models and Mouse Genetic Models of Chronic Liver Inflammation

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