Development of hepatocellular carcinoma in mice with disrupted peroxisomal fatty acyl-CoA oxidase gene

C. Y. Fan*, H. Sakuraba, Anjana V Yeldandi, Sambasiva Rao Musunuri, Janardan K Reddy

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Hepatocellular carcinoma is one of the commonest malignant diseases in southeast Asia and sub-Saharan Africa, where hepatitis B and Aflatoxins are thought to be the underlying etiologies. Even though it is a relatively rare disease in America and most of Europe, there has been a small, but dramatic increase in incidence for the last several decades probably due to rising incidence of chronic alcoholism. Alcoholic liver disease represents one of the commonest public health hazards in Western countries and it is characterized by a spectrum of disorders, ranging from fatty changes at the beginning, followed by inflammatory infiltrates and lipogranutoma formation (alcoholic hepatitis) to eventual development of cirrhosis and hepatic cancer. For the last five years, mouse models for hepatocellular carcinoma have been established in different groups by generating mice transgenic for HBV surface antigen, TGF-±, SV40 T-antigen, c-H-ras, and IGF-II, and this has dramatically advanced our understanding of the mechanisms of hepatocarcinogenesis at the molecular and genetic levels. Here, we report the development of hepatocellular carcinoma in mice with disrupted peroxisomal acyl-CoA oxidase gene (ACOX) generated through homologous recombination. These mice are devoid of ACOX protein, the first and rate-limiting enzyme of the peroxisomal fatty acid β-oxidation pathway, developed microvesicular fatty changes in hepatocytes during their early life, followed by marked acute and chronic inflammation, lipogranuloma formation and regenerative nodule formation at about six months of age and developed hepatocellular carcinoma by 8-14 months of age. By comparison, the heterozygous and wild-type littermates of the same age do not show any tumor formation. This animal model should be valuable in illustrating the possible links between prolonged fatty change, regeneration and tumor formation in the liver.

Original languageEnglish (US)
JournalFASEB Journal
Volume11
Issue number3
StatePublished - Dec 1 1997

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ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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