Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma

Authors

  • Atsushi Umemura,

    1. Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    2. Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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  • Yoshito Itoh,

    1. Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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  • Katsuhiko Itoh,

    1. Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Kanji Yamaguchi,

    1. Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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  • Tomoki Nakajima,

    1. Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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  • Hiroaki Higashitsuji,

    1. Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Hitoshi Onoue,

    1. Department of Nutritional Science, Faculty of Health and Welfare, Seinan Jo Gakuin University, Kitakyushu, Japan
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  • Manabu Fukumoto,

    1. Department of Pathology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
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  • Takeshi Okanoue,

    1. Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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  • Jun Fujita

    Corresponding author
    1. Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    • Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
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    • fax: (81) 75-751-4977.


  • Potential conflict of interest: Nothing to report.

Abstract

Gankyrin (also known as PSMD10) is a liver oncoprotein that interacts with multiple proteins including MDM2 and accelerates degradation of the tumor suppressors p53 and Rb. We produced a monoclonal anti-gankyrin antibody and immunohistochemically assessed the clinicopathological significance of gankyrin overexpression in 43 specimens of human hepatocellular carcinoma (HCC). Specific cytoplasmic staining for gankyrin was observed in 62.8% (27/43) of HCCs, which was significantly associated with low TNM stage (P = 0.004), no capsular invasion (P = 0.018), no portal venous invasion (P = 0.008), and no intrahepatic metastasis (P = 0.012). The cumulative survival rate of patients with gankyrin-positive HCC was significantly higher than that with gankyrin-negative HCC (P = 0.037). p53 and MDM2 were positively stained by antibodies in 30.2% and 23.3%, respectively, of HCCs, but neither was inversely associated with gankyrin expression. In the Huh-7 human HCC cell line, overexpression of gankyrin up-regulated expression of insulin-like growth factor binding protein 5 (IGFBP-5), whereas suppression of gankyrin expression by siRNA down-regulated it. Supression of IGFBP-5 expression inhibited proliferation of Huh-7 cells as well as U-2 OS osteosarcoma cells. In HCC specimens, positive staining for IGFBP-5 was observed by immunohistochemistry in 41.9% (18/43), and the level of expression was significantly correlated with that of gankyrin (rho = 0.629, P < 0.001). Conclusion: These results suggest that gankyrin plays an oncogenic role(s) mainly at the early stages of human hepatocarcinogenesis, and that IGFBP-5 inducible by gankyrin overexpression may be involved in it. (HEPATOLOGY 2008.)

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