The role of PGE 2 -associated inflammatory responses in gastric cancer development
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REVIEW
The role of PGE2-associated inflammatory responses in gastric cancer development Hiroko Oshima & Masanobu Oshima
Received: 1 September 2012 / Accepted: 30 September 2012 / Published online: 11 October 2012 # Springer-Verlag Berlin Heidelberg 2012
Abstract 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
This article is a contribution to the special issue on Inflammation and Cancer Guest Editor: Takuji Tanaka H. Oshima : M. Oshima (*) Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan e-mail: [email protected]
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 PGE2associated inflammatory responses promote in vivo gastric tumorigenesis via several different molecular mechanisms. Keywords Gastric cancer . Inflammation . COX-2 . PGE2 . EGFR . MicroRNA
Introduction It has been shown that approximately 15–20 % of malignant cancers are associated with chronic infection [1, 2]. For example, infection with Helicobacter pylori, hepatitis C virus, and human papilloma virus is closely associated with the development of gastric cancer, hepatocellular carcinoma, and cervical cancer, respectively. On the other hand, it has also been reported that tobacco smoke and obesity contribute to tumor development through induction of inflammatory responses in the lungs and liver, respectively [3
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