Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss

Authors

  • Shelli M. Morris,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
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  • Ji Yeon Baek,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
    2. Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
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  • Amanda Koszarek,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
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  • Samornmas Kanngurn,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
    2. Department of Pathology, Prince of Songkla University, Hat Yai, Thailand
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  • Sue E. Knoblaugh,

    1. Animal Health Resources, Fred Hutchinson Cancer Research Center, Seattle, WA USA
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  • William M. Grady

    Corresponding author
    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
    2. Department of Medicine, University of Washington Medical School, Seattle, WA USA
    • Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Ave. N, Mailstop D4-100, Seattle, WA 98109-1024
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    • fax: 206-667-2917


  • Potential conflict of interest: Nothing to report.

Abstract

Hepatocellular carcinoma (HCC) results from the accumulation of deregulated tumor suppressor genes and/or oncogenes in hepatocytes. Inactivation of TP53 and inhibition of transforming growth factor-beta (TGF-β) signaling are among the most common molecular events in human liver cancers. Thus, we assessed whether inactivation of TGF-β signaling, by deletion of the TGF-β receptor, type II (Tgfbr2), cooperates with Trp53 loss to drive HCC formation. Albumin-cre transgenic mice were crossed with floxed Trp53 and/or floxed Tgfbr2 mice to generate mice lacking p53 and/or Tgfbr2 in the liver. Deletion of Trp53 alone (Trp53KO) resulted in liver tumors in approximately 41% of mice by 10 months of age, whereas inactivation of Tgfbr2 alone (Tgfbr2KO) did not induce liver tumors. Surprisingly, deletion of Tgfbr2 in the setting of p53 loss (Trp53KO;Tgfbr2KO) decreased the frequency of mice with liver tumors to around 17% and delayed the age of tumor onset. Interestingly, Trp53KO and Trp53KO;Tgfbr2KO mice develop both HCC and cholangiocarcinomas, suggesting that loss of p53, independent of TGF-β, may affect liver tumor formation through effects on a common liver stem cell population. Assessment of potential mechanisms through which TGF-β signaling may promote liver tumor formation in the setting of p53 loss revealed a subset of Trp53KO tumors that express increased levels of alpha-fetoprotein. Furthermore, tumors from Trp53KO mice express increased TGF-β1 levels compared with tumors from Trp53KO;Tgfbr2KO mice. Increased phosphorylated Smad3 and ERK1/2 expression was also detected in the tumors from Trp53KO mice and correlated with increased expression of the TGF-β responsive genes, Pai1 and Ctgf. Conclusion: TGF-β signaling paradoxically promotes the formation of liver tumors that arise in the setting of p53 inactivation. (HEPATOLOGY 2012)

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