The role of PGE2-associated inflammatory responses in gastric cancer development
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- Oshima, H. & Oshima, M. Semin Immunopathol (2013) 35: 139. doi:10.1007/s00281-012-0353-5
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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 E2 (PGE2), and plays a key role in both inflammation and cancer. It has been demonstrated that inhibition of COX-2 and PGE2 receptor signaling results in the suppression of tumor development in a variety of animal models. However, the molecular mechanisms underlying COX-2/PGE2-associated inflammation in carcinogenesis have not yet been fully elucidated. In order to study the role of PGE2-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/PGE2 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/PGE2 pathway and Wnt signaling. Expression analyses using these in vivo models have revealed novel mechanisms of the inflammatory responses underlying gastric cancer development. PGE2-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, PGE2-associated inflammation downregulates tumor suppressor microRNA, miR-7, in gastric cancer cells, which suppresses epithelial differentiation. These results indicate that PGE2-associated inflammatory responses promote in vivo gastric tumorigenesis via several different molecular mechanisms.