Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas

Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas

^*Institut National de la Santé et de la Recherche Médicale U129, Institut Cochin de Génétique Moléculaire, Université Paris V René Descartes, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France; ^‡Institut National de la Santé et de la Recherche Médicale U163, Institut Pasteur, 28 rue du Docteur Roux, 75015 Paris, France; ^§Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; and ^¶Hôpital du Kremlin Biêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France

Edited by Walter Bodmer, University of Oxford, Oxford, United Kingdom, and approved May 12, 1998 (received for review March 2, 1998)

Abstract

Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-β-catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the β-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras. Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the β-catenin gene similar to those found in colon cancers and melanomas. These alterations in the β-catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of β-catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of β-catenin in the nucleus. Thus alterations in the β-catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-β-catenin pathway is a major event in the development of HCC in humans and mice.

Footnotes

↵ † A.d.L.C. and B.R. contributed equally to this work.
↵ ‖ To whom reprint requests should be addressed. e-mail: perret{at}icgm.cochin.inserm.fr.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: HCC, hepatocellular carcinoma; APC, adenomatous polyposis coli; GSK-3β, glycogen synthase kinase-3β; RT-PCR, reverse transcription–PCR; DGGE, denaturing gradient gel electrophoresis; L-PK, L-type pyruvate kinase.