Abstract
Perturbations to the Wnt signaling pathway have been implicated in a large proportion of human hepatocellular carcinomas (HCCs). Activating beta-catenin mutations and loss of function mutations in Axin1 are thought to be functionally equivalent. We examined the Wnt pathway in HCC by comparing the expression of beta-catenin target genes and the level of beta-catenin-dependent transcriptional activation, in 45 HCC tumors and four cell lines. Among these samples, beta-catenin and AXIN1 were mutated in 20 and seven cases, respectively. We found a significant correlation between activated beta-catenin mutations and overexpression of mRNA for the target genes glutamine synthetase (GS), G-protein-coupled receptor (GPR)49 and glutamate transporter (GLT)-1 (P=0.0001), but not for the genes ornithine aminotransferase, LECT2, c-myc and cyclin D1. We also showed that GS is a good immunohistochemical marker of beta-catenin activation in HCC. However, we observed no induction of GS, GPR49 or GLT-1 in the five inactivated Axin1 tumors. Beta-catenin-dependent transcriptional activation in two Axin1-mutated HCC cell lines was much weaker than in beta-catenin-mutated cell lines. Our results strongly suggest that in HCC, contrary to expectation, the loss of function of Axin1 is not equivalent to the gain of function of beta-catenin. Our results also suggest that the tumor suppressor function of Axin1 in HCC may be related to another, non-Wnt pathway.
Highlights
The Wnt signaling pathway regulates cellular proliferation and differentiation, and it is essential for the development and morphogenesis (Giles et al, 2003)
The role of b-catenin is crucial and abnormal b-catenin activation has been found in many different types of cancer, such as colon cancers almost exclusively associated with inactivating mutations in APC, and various b-catenin mutations are found in human tumors (Giles et al, 2003)
The seven b-catenin target genes included two canonical b-catenin target genes, c-myc and cyclinD1 (He et al, 1998; Tetsu and McCormick, 1999), and five recently identified b-catenin target genes overexpressed in human Hepatocellular carcinoma (HCC): glutamine synthetase (GS), the glutamate transporter (GLT)-1, ornithine aminotransferase (OAT) (Cadoret et al, 2002), an orphan G-protein-coupled receptor (GPR)49 (Yamamoto et al, 2003) and a chemokine-like protein LECT2 (Ovejero et al, 2004)
Summary
The Wnt signaling pathway regulates cellular proliferation and differentiation, and it is essential for the development and morphogenesis (Giles et al, 2003). Chromosome-stable HCCs are associated with HCV infection, high alcohol consumption and may contain b-catenin-activating mutations (20–40% of the tumors) (Miyoshi et al, 1998; de La Coste et al, 1998; Legoix et al, 1999; Laurent-Puig et al, 2001). We measured the expression level of seven b-catenin target genes in human HCCs that had mutations in either b-catenin or Axin1.
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