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Differential expression of E‐prostanoid receptors in human hepatocellular carcinoma
Author(s) -
Breinig Marco,
Rieker Ralf,
Eiteneuer Eva,
Wertenbruch Tina,
Haugg Anke Maria,
Helmke Burkhard Maria,
Schirmacher Peter,
Kern Michael André
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23098
Subject(s) - hccs , receptor , biology , prostanoid , viability assay , apoptosis , cancer research , hepatocellular carcinoma , medicine , biochemistry
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. © 2007 Wiley‐Liss, Inc.