• Open Access

Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β-catenin/TCF

Authors

  • Yuichi Torisu,

    1. Genome Science Division and
    2. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8471;
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  • Akira Watanabe,

    1. Genome Science Division and
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  • Aya Nonaka,

    1. Genome Science Division and
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  • Yutaka Midorikawa,

    1. Genome Science Division and
    2. Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655;
    3. Teikyo University School of Medicine, Mizonokuchi Hospital, 3-8-3, Mizonokuchi, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8507;
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  • Masatoshi Makuuchi,

    1. Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655;
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  • Takahiro Shimamura,

    1. Genome Science Division and
    2. The First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu-shi, Shizuoka 431-3192;
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  • Haruhiko Sugimura,

    1. The First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu-shi, Shizuoka 431-3192;
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  • Atsushi Niida,

    1. Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032;
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  • Tetsu Akiyama,

    1. Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032;
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  • Hiroko Iwanari,

    1. Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904;
    2. Perseus Proteomics, 4-7-6, Komaba, Meguro-ku, Tokyo 153-0041, Japan
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  • Tatsuhiko Kodama,

    1. Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904;
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  • Mikio Zeniya,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8471;
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  • Hiroyuki Aburatani

    Corresponding author
    1. Genome Science Division and
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To whom correspondence should be addressed. E-mail: haburata-tky@umin.ac.jp

Abstract

The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of β-catenin protein: all 10 HCC with high intracellular β-catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular β-catenin had high NOTUM expression (P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant-negative mutant of TCF4, a β-catenin partner. In vivo binding of the β-catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of β-catenin/TCF4 and is upregulated in Wnt/β-catenin signaling-activated HCC. (Cancer Sci 2008; 99: 1139–1146)

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