Survivin overexpression in hepatocellular carcinoma is associated with p53 dysregulation

Background: Survivin is a recently described anti-apoptotic protein that is suppressed by wild-type p53 and is overexpressed in 41-70% of hepatocellular carcinomas from Asia. Two alternatively spliced transcripts have also been described: anti-apoptotic survivin-ΔEx3 and non-anti-apoptotic survivin-2B. Survivin splice variant expression has not been studied in HCC, and little is known about survivin expression in hepatocellular carcinomas arising in other parts of the world, where risk factors are often different than they are in Asia. Aim of the Study: We studied survivin mRNA and protein expression in a United States cohort of hepatocellular carcinomas and correlated the findings with p53 immunopositivity. Methods: RT-PCR was performed for survivin, survivin-2B, and survivin-ΔEx3 in 20 HCCs and one intrahepatic cholangiocarcinoma. Expression levels of total survivin were evaluated with real-time PCR. Protein expression was examined by immunohistochemistry. Results: Survivin was the major transcript, and all transcripts were present in all normal and neoplastic tissues; 11/20 (55%) HCCs and the one cholangiocarcinoma showed twofold or greater overexpression of survivin. Next, we examined survivin and p53 protein expression by immunohistochemistry on a separate series of 79 HCC, 13 fibrolamellar carcinomas, and 15 hepatic adenomas; 14/79 (17%) HCC, but none of the fibrolamellar carcinomas or hepatic adenomas, showed survivin protein overexpression, and 25/79 HCC (32%) showed abnormal nuclear accumulation of p53, which correlated with increased survivin expression. Conclusions: All three survivin transcripts are present in normal liver and HCC. Survivin is the dominant transcript in HCC and is overexpressed in 55% of cases. Survivin protein overexpression is associated with aberrant p53 nuclear positivity.