Differential expression of E-prostanoid receptors in human hepatocellular carcinoma

Int J Cancer. 2008 Feb 1;122(3):547-57. doi: 10.1002/ijc.23098.


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 (EP(1-4)). 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 EP(1-4)-receptors was analyzed. Western immunoblot analyses were performed to confirm the expression in HCC cell lines. The effects of EP(1-4)-receptor antagonism on cell viability and apoptosis were investigated using MTT-assays and FACS-analyses, respectively. COX-2, mPGES-1 and -2 and EP(1-4)-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 EP(1-3) -receptors and mPGES-1 and -2 was found in DNs compared to HCCs. Selectively antagonizing EP(1)- and EP(3)-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 EP(1-3)-receptors occurs. Of clinical interest, selectively antagonizing EP(1)- and EP(3)-receptors may provide a novel systemic therapeutic approach to the treatment of HCCs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Survival / drug effects
  • Cyclooxygenase 2 / metabolism*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Intramolecular Oxidoreductases / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / etiology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Prostaglandin-E Synthases
  • Receptors, Prostaglandin E / metabolism*
  • Tissue Array Analysis


  • Receptors, Prostaglandin E
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases