Expression of the ELAV-like protein HuR in human prostate carcinoma is an indicator of disease relapse and linked to COX-2 expression

Abstract

The human ELAV-like protein HuR is involved in the stabilization of the mRNAs of a group of genes implicated in the regulation of cellular growth, angiogenesis and rapid inflammatory response. HuR is a nuclear shuttling protein, translocating bound mRNAs from the nucleus to the cytoplasm. We have previously observed an increased expression of cyclooxygenase-2 (COX-2) in prostate cancer while cell culture studies have shown that HuR stabilizes the mRNA of COX-2. Based on these mechanistic data, we aimed to investigate the role of HuR in prostate cancer by a tissue-based analysis combined with functional evaluation using a cell culture approach. Investigating 104 primary prostate carcinomas by immunohistochemistry, we found HuR expression to be shifted from a nuclear staining in normal prostate glands to a cytoplasmic staining in carcinoma tissue (p<0.0001). Cytoplasmic HuR expression was significantly correlated with COX-2 expression (p=0.005). Loss of nuclear HuR expression was an indicator of earlier PSA-relapse both in univariate (p=0.04) and multivariate survival analysis (p=0.04). HuR inhibition by Leptomycin B reduced the inducibility of COX-2 in PC-3 prostate cancer cells. We found that the subcellular localization of HuR is deregulated in a subset of prostate carcinomas, and that this deregulation is linked to an altered expression of the tumorigenic COX-2 protein as well as to an adverse patient prognosis. Our results point to a potential prognostic role of HuR expression in prostate cancer diagnostics and propose HuR as a future therapeutic target in prostate cancer therapy.