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 beta-catenin protein: all 10 HCC with high intracellular 
beta-catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) 
without intracellular beta-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 beta-catenin partner. In vivo binding of 
the beta-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 beta-catenin/TCF4 and is upregulated in Wnt/beta-catenin 
signaling-activated HCC.