Protease-activated receptor-2 regulates cell proliferation and enhances cyclooxygenase-2 mRNA expression in human pancreatic cancer cells.
OBJECTIVE
Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is activated by trypsin. Recent studies have suggested that PAR-2 activity correlates with inflammatory processes and cell proliferation and that PAR-2 activation in non-neoplastic cells induces expression of cyclooxygenase-2 (COX-2). In the present study, we examined whether PAR-2 activation regulates cell proliferation and COX-2 expression by pancreatic cancer cells.


METHODS
We analyzed PAR-2 expression immunohistochemically in 40 intraductal papillary-mucinous neoplasms (IPMNs) and 73 invasive ductal carcinomas (IDCs) of the pancreas. We used four pancreatic cancer cell lines (Panc1, T3M4, BxPC3, and MIApaca2) to measure cell proliferation and COX-2 mRNA expression after PAR-2 activation.


RESULTS
PAR-2 protein was detected immunohistochemically in 85.0% of IPMNs and 65.8% of IDCs. Trypsin and a PAR-2 agonist peptide, SLIGKV, stimulated proliferation of each cell line in a dose-dependent manner. Exposure of cells to anti-PAR-2 neutralizing antibody prior to PAR-2 activation suppressed cell proliferation. In COX-2-positive cell lines (T3M4 and BxPC3), PAR-2 activation significantly increased COX-2 mRNA expression.


CONCLUSIONS
Our results suggest that PAR-2 activation is associated with cell proliferation and COX-2 expression in pancreatic cancer cells. Blockade of the PAR-2 signaling pathway may be a novel strategy for suppressing pancreatic tumor growth.
Yada
Kazuhiro
K
Department of Surgery I, Oita University Faculty of Medicine, Oita, Japan. kazuyada@med.oita-u.ac.jp
Shibata
Kohei
K
Matsumoto
Toshifumi
T
Ohta
Masayuki
M
Yokoyama
Shigeo
S
Kitano
Seigo
S
D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051546:Cyclooxygenase 2; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044464:Receptor, PAR-2 / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D008565:Membrane Proteins; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases