Protease-activated receptor-2 regulates cyclooxygenase-2 expression in human bile duct cancer via the pathways of mitogen-activated protein kinases and nuclear factor kappa B.

Abstract

BACKGROUND/PURPOSE:

Recent studies have suggested that protease-activated receptor-2 (PAR-2) activity correlates with cell proliferation and tumor growth, and its activation induces expression of cyclooxygenase-2 (COX-2). However, no previous reports have investigated PAR-2 signaling pathways in bile duct cancer. The aim of this study was to determine whether PAR-2 activation can regulate COX-2 expression via mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) in human bile duct cancer cells.

METHODS:

We immunohistochemically examined PAR-2 and COX-2 expression in 104 resected human specimens of extrahepatic bile duct cancer. We then determined how inhibitors of MAPKs and NF-κB signaling pathways influence COX-2 expression under PAR-2 activation in HuCCT1 and TKKK, human bile duct cancer cell lines.

RESULTS:

PAR-2 and COX-2 proteins were immunohistochemically recognized in 63 and 57% of specimens and were significantly correlated. PAR-2 agonist peptide activated mRNA and protein expression of COX-2 in HuCCT1 and TKKK. Pharmacologic blockade of p44/42 or p38 MAPK significantly inhibited PAR-2-activated mRNA and protein expression of COX-2 in both cells. COX-2 protein expression was also inhibited by the blocker of NF-κB pathway in both cells.

CONCLUSIONS:

PAR-2 may regulate COX-2 expression in human bile duct cancer via the MAPKs and NF-κB pathways.

• Authors: Hidetoshi Eguchi, Kentaro Iwaki, Kohei Shibata, Tadashi Ogawa, Masayuki Ohta, Seigo Kitano
• Journal: Journal of hepato-biliary-pancreatic sciences (J Hepatobiliary Pancreat Sci) Vol. 18 Issue 2 Pg. 147-53 (Mar 2011) ISSN: 1868-6982 [Electronic] Japan
• PMID: 20740367 (Publication Type: Comparative Study, Journal Article)

Chemical References

• NF-kappa B
• RNA, Messenger
• Receptor, PAR-2
• Cyclooxygenase 2
• Mitogen-Activated Protein Kinases

Topics

• Bile Duct Neoplasms (enzymology, genetics, pathology)
• Bile Ducts, Extrahepatic (metabolism, pathology)
• Cell Line, Tumor
• Cyclooxygenase 2 (biosynthesis, genetics)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Polymerase Chain Reaction
• RNA, Messenger (biosynthesis, genetics)
• Receptor, PAR-2 (genetics, metabolism)
• Signal Transduction (physiology)