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  • Original Article
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Hepatocellular carcinoma in Txnip-deficient mice

Oncogene volume 25, pages 3528–3536 (2006)Cite this article

Abstract

The molecular pathogenesis and the genetic aberrations that lead to the progression of hepatocellular carcinoma (HCC) are largely unknown. Here, we demonstrate that the thioredoxin interacting protein (Txnip) gene is a candidate tumor suppressor gene in vivo. We previously showed that the recombinant inbred congenic strain HcB-19 has a spontaneous mutation of the Txnip gene, and we now show that the strain has dramatically increased incidence of HCC, and that the HCC cosegregates with the Txnip mutation. Approximately 40% of the Txnip-deficient mice developed hepatic tumors with an increased prevalence in male mice. Visible tumors develop as early as 8 months of age. Histological analysis confirmed the morphology of HCC in the Txnip-deficient mice. Molecular markers of HCC, α-fetoprotein and p53, were increased in tumors of Txnip-deficient mice. The upregulation of p53 preceded tumor development; however, bromodeoxyuridine (BrdU) labeling of normal hepatic tissue of Txnip-deficient mice did not reveal increased cell proliferation. Finally, microarray analyses of tumor, non-tumor adjacent, and normal tissue of Txnip-deficient mice highlighted the genetic differences leading to the predisposition and onset of HCC. Our findings suggest that Txnip deficiency is sufficient to initiate HCC and suggest novel mechanisms in hepatocarcinogenesis.

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Acknowledgements

This study was supported by NIH Grant HL28481 (AJL) and the Johnson Comprehensive Cancer Center, UCLA.

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Authors and Affiliations

  1. Departments of Human Genetics, Medicine, Molecular Biology Institute, and Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, 47-123 CHS, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    S S Sheth, A Ghazalpour, C K Thipphavong & A J Lusis

  2. Biomedical Research Division, Beckman Coulter, Inc., Fullerton, CA, USA

    J S Bodnar

  3. Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Meguro-ku, Tokyo, Japan

    S Tsutsumi & H Aburatani

  4. Department of Microbiology and Immunology, University of California San Francisco, GW Hooper Foundation, San Francisco, CA, USA

    A D Tward

  5. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, USA

    P Demant

  6. Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology 34, University of Tokyo, Meguro-ku, Tokyo, Japan

    T Kodama

  7. UCLA Johnson Comprehensive Cancer Center, Los Angeles, CA, USA

    A J Lusis

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  1. S S Sheth
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Correspondence to A J Lusis.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Sheth, S., Bodnar, J., Ghazalpour, A. et al. Hepatocellular carcinoma in Txnip-deficient mice. Oncogene 25, 3528–3536 (2006). https://doi.org/10.1038/sj.onc.1209394

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