Open AccessHuman homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β‐catenin/TCF
Author(s) -
Torisu Yuichi,
Watanabe Akira,
aka Aya,
Midorikawa Yutaka,
Makuuchi Masatoshi,
Shimamura Takahiro,
Sugimura Haruhiko,
Niida Atsushi,
Akiyama Tetsu,
Iwanari Hiroko,
Kodama Tatsuhiko,
Zeniya Mikio,
Aburatani Hiroyuki
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00814.x
Subject(s) - wnt signaling pathway , biology , catenin , gene , tcf4 , microbiology and biotechnology , cancer research , genetics , gene expression , promoter
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)