1. ¹INSERM U674 IFR105, Paris Saint-Louis, CEPH, Paris, France
2. ²Institut Cochin, INSERM U567, CNRS UMR 8104, Université Paris5 René Descartes, Département EMC, Paris, France
3. ³Département d'Hepatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
4. ⁴Service d'Anatomie Pathologique, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
5. ⁵GREF Inserm E362, Université Bordeaux 2, Bordeaux, France
6. ⁶Service de Chirurgie Digestive, Hôpital Saint-André CHU Bordeaux, Bordeaux, France

Correspondence: Dr C Perret, Institut Cochin, INSERM U567, CNRS UMR 8104, Université Paris5 René Descartes, Département EMC, Faculté de Médecine Cochin Port Royal, 24, Bat Faculté, Rue du Faubourg Saint Jacques, 75014 Paris, France. E-mail: perret@cochin.inserm.fr

⁷Equal second authors.

Received 22 March 2006; Revised 22 May 2006; Accepted 14 June 2006; Published online 11 September 2006.

Abstract

Perturbations to the Wnt signaling pathway have been implicated in a large proportion of human hepatocellular carcinomas (HCCs). Activating -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 -catenin target genes and the level of -catenin-dependent transcriptional activation, in 45 HCC tumors and four cell lines. Among these samples, -catenin and AXIN1 were mutated in 20 and seven cases, respectively. We found a significant correlation between activated -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 -catenin activation in HCC. However, we observed no induction of GS, GPR49 or GLT-1 in the five inactivated Axin1 tumors. -Catenin-dependent transcriptional activation in two Axin1-mutated HCC cell lines was much weaker than in -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 -catenin. Our results also suggest that the tumor suppressor function of Axin1 in HCC may be related to another, non-Wnt pathway.