Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas

作者：Zucman Rossi J; Benhamouche S; Godard C; Boyault S; Grimber G; Balabaud C; Cunha A S; Bioulac Sage P; Perret C^*

来源：Oncogene, 2007, 26(5): 774-780.

DOI：10.1038/sj.onc.1209824

• hepatocellular carcinoma
• beta-catenin
• Axin1
• target genes
• Wnt pathway

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 b-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 b-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 b-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.

• 出版日期2007-2