β-catenin and cyclin D1 expression in human hepatocellular carcinoma

To understand the nature and roles of mutated β-catenin in human hepatocellular carcinomas (HCCs), 57 cases of surgically resected HCCs were studied. DNAs extracted from each tumor were examined for somatic mutations of exon 3, and the protein expressions of β-catenin, cyclin D1, and Ki-67 were observed by immunohistochemical staining. β-catenin mutations in exon 3 were detected in 10 (17.5%) out of 57 HCCs, including nine missense mutations and one deletion mutation. All of the cases with gene alterations had the anti-HCV antibody, and tested negative for the HBs antigen in the sera. All of the mutations occurred at the serine/threonine phosphorylation sites of glycogen synthase kinase-3β (GSK-3β) or their neighboring residues. Significant correlation with intracellular expression (p=0.00055) was shown in the HCCs harboring β-catenin mutations. The intracellular accumulation of β-catenin showed significant correlation with the cyclin D1 expression (p=0.00858), and with a higher proliferation index (p=0.00072). In addition, the β-catenin mutations showed significant association with the cyclin D1 expression (p=0.0424). These results suggest that accumulated β-catenin proteins may bind to the lymphocyte enhancer binding factor-1 (LEF-1), form the β-catenin/LEF-1 complex, and stimulate such promoters regulating the cell cycle as the cyclin D1 gene. This is the first report to demonstrate a significant correlation between β-catenin and the cyclin D1 expression in human HCCs.