PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma

Abstract

The peptidyl-proplyl-isomerase, PIN1, upregulates β-catenin by inhibiting its interaction with APC. β-catenin accumulation occurs in about 70% of hepatocellular carcinoma (HCC), of which only 20% are due to β-catenin mutations. The role of PIN1 in β-catenin upregulation in HCC was investigated. PIN1 was shown to be overexpressed in more than 50% of HCC. All cases with PIN1 overexpression also showed β-catenin accumulation, with 68% of cases showing concomitant β-catenin and cyclin D1 accumnlation. PIN1 was shown to contribute to β-catenin and cyclin D1 overexpression directly by in vitro cell-line transfection experiments. Finally, we showed that PIN1 overexpression and β-catenin gene mutations appeared to be mutually exclusive events, leading to β-catenin accumulation in HCC. These results showed that PIN1 overexpression leading to β-catenin accumulation might be a critical event in hepatocarcinogenesis, and that PIN1 is a potential target for therapeutic intervention in HCC.