PIN1 is over-expressed in hepatocellular carcinoma (HCC) and correlates with an increased beta-catenin and cyclin D1 protein levels

Abstract

INTRODUCTION: In hepatocellular carcinoma, the expression of beta-catenin and cyclin D1 is increased, which may be of pathogenetic significance. As mutations of the beta-catenin gene are only found in around 20% of cases, other factors are involved in the accumulation of beta-catenin and cyclin D1. PIN1, a peptidyl-proplyl-isomerase, has been shown to stabilize both beta-catenin and cyclin D1, and to up-regulate cyclin D1 gene expression. We hypothesize that the beta-catenin and cyclin D1 accumulation in some of the HCC is contributed by PIN over-expression. METHODS: The expression of PIN1 in 23 paired-samples of neoplastic and non-neoplastic liver tissues was examined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and Western blot analysis. Immunohistochemistry was also performed on another 28 paired archival samples of HCC to detect PIN1, beta-catenin and cyclin D1 expression. RESULTS: Compared with paired non-neoplastic liver tissues, 12 of 23 (52%) HCC samples showed an increase in PIN1 expression by semi-quantitative RT-PCR. These cases also showed beta-catenin accumulation, and sequencing of exon 3 of the beta-catenin gene did not show any mutation. Together with the archival materials, PIN1 was found to be over-expressed by immunohistochemistry and Western blot analysis in 26 of 45 tumors (58%), all of which had concomitant accumulation of beta-catenin. Another 5 cases had beta-catenin accumulation without PIN1 over-expression, so that the overall frequency of beta-catenin over-expression was 68% (31/45). In 3 cases with beta-catenin accumulation but no PIN1 over-expression, 2 cases showed mutation in the exon 3 of the beta-catenin gene. Finally, 19 of 26 cases with PIN1 over-expression also had increase in cyclin D1 expression. CONCLUSION: PIN1 expression is increased in a significant proportion of HCC. There is a positive correlation between PIN1, and beta -catenin and cyclin D1 expression, which suggests that PIN1 may be critically involved in hepatocarcinogenesis.