Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation

Inappropriate activation of the Wnt pathway resulting from beta-catenin gen e alterations has recently been implicated in the development of hepatocell ular carcinoma (HCC). To explore the in vivo effects of mutated beta-cateni n, HCC specimens from 32 patients carrying one or several tumors were scree ned for somatic mutations in exon 3 of the beta-catenin gene, and the expre ssion and subcellular localization of beta-catenin was studied by immunohis tochemistry. Missense mutations or interstitial deletions in beta-catenin e xon 3 were detected in 12 of 35 (34%) HCC samples. After immunostaining, mo st tumors exhibited increased membranous and/or cytoplasmic expression of b eta-catenin compared with adjacent nontumoral Liver. Strong nuclear accumul ation of beta-catenin was observed either focally or uniformly in 15 of 35 (43%) tumor specimens, but not in cirrhotic nodules or dysplastic liver tel ls in adjacent Liver. Aberrant nuclear expression of beta-catenin was signi ficantly associated with the presence of mutations in the beta-catenin gene (P < 0.005). Moreover, nuclear beta-catenin staining correlated significan tly with increased Ki-67 proliferative index in tumor (P < 0.001) and seeme d to be associated with poor outcome in patients with HCC. In conclusion, o ur data indicate that activation of the Wnt/beta-catenin pathway in. HCC re sults mainly from somatic mutations in the beta-catenin gene and may promot e tumor progression by stimulating tumor cell proliferation.