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 PGE2 synthesis. PGE2 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. © 2007 Wiley‐Liss, Inc.