The role of PGE2-associated inflammatory responses in gastric cancer development.
Accumulating evidence indicates that inflammation plays a critical role in cancer development. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme for prostanoid biosynthesis, including prostaglandin E(2) (PGE(2)), and plays a key role in both inflammation and cancer. It has been demonstrated that inhibition of COX-2 and PGE(2) receptor signaling results in the suppression of tumor development in a variety of animal models. However, the molecular mechanisms underlying COX-2/PGE(2)-associated inflammation in carcinogenesis have not yet been fully elucidated. In order to study the role of PGE(2)-associated inflammatory responses in tumorigenesis, it is important to use in vivo mouse models that recapitulate human cancer development from molecular mechanisms with construction of tumor microenvironment. We have developed a gastritis model (K19-C2mE mice) in which an inflammatory microenvironment is constructed in the stomach via induction of the COX-2/PGE(2) pathway. We also developed a gastric cancer mouse model (Gan mice) in which the mice develop inflammation-associated gastric tumors via activation of both the COX-2/PGE(2) pathway and Wnt signaling. Expression analyses using these in vivo models have revealed novel mechanisms of the inflammatory responses underlying gastric cancer development. PGE(2)-associated inflammatory responses activate epidermal growth factor receptor (EGFR) signaling through the induction of EGFR ligands and ADAMs that release EGFR ligands from the cell membrane. In Gan mice, a combination treatment with EGFR and COX-2 inhibitors significantly suppresses gastric tumorigenesis. Moreover, PGE(2)-associated inflammation downregulates tumor suppressor microRNA, miR-7, in gastric cancer cells, which suppresses epithelial differentiation. These results indicate that PGE(2)-associated inflammatory responses promote in vivo gastric tumorigenesis via several different molecular mechanisms.
Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Hiroko
H
Oshima
Masanobu
M
Oshima
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000276:immunology*
D051546:Cyclooxygenase 2; D015232:Dinoprostone; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C549242:MIRN7-1 microRNA, human; C549243:MIRN7 microRNA, mouse; C077623:Ptgs2 protein, mouse; C496540:PTGS2 protein, human