Differential expression of E-prostanoid receptors in human hepatocellular carcinoma

Recent studies have shown that inhibition of cyclooxygenases (e.g. COX-2) exerts antitumorigenic effects on hepatocellular carcinomas (HCCs), which are to a significant extent due to the abrogation of PGE(2) synthesis. PGE(2) acts via differentially regulated prostaglandin receptors (EP1-4). Our study was designed to investigate the expression pattern of EP-receptors in HCCs and to evaluate the therapeutic potential of selective EP-receptor antagonists. Using tissue microarrays including a total of 14 control livers, 17 liver cirrhoses, 22 premalignant dysplastic nodules (DNs) and 162 HCCs with different histological grades, the expression of COX-2, mPGES-1 and -2 and EP1-4-receptors was analyzed. Western immunoblot analyses were performed to confirm the expression in HCC cell lines. The effects of EP1-4-receptor antagonism on cell viability and apoptosis were investigated using MTT-assays and FACS-analyses, respectively. COX-2, mPGES-1 and -2 and EP1-4-receptors were expressed in all HCC tissues. COX-2 expression was highest in DNs and declined with loss of HCC-differentiation. With respect to COX-2 expression, a converse expression of EP1-3-receptors and mPGES-1 and -2 was found in DNs compared to HCCs. Selectively antagonizing EP1- and EP3-receptors reduced the viability of HCC cells in a dose-dependent manner, which was associated with apoptosis induction. Our results suggest a differential regulation of EP-receptor subtype expression with dedifferentiation of HCCs in which a converse expression pattern for COX-2 in comparison to EP1-3-receptors occurs. Of clinical interest, selectively antagonizing EP1- and EP3-receptors may provide a novel systemic therapeutic approach to the treatment of HCCs. (c) 2007 Wiley-Liss, Inc.