title: Activation of epidermal growth factor receptor signaling by the prostaglandin E(2) receptor EP4 pathway during gastric tumorigenesis.
abstract: Cyclooxygenase-2 (COX-2) plays an important role in tumorigenesis through prostaglandin E(2) (PGE(2)) biosynthesis. It has been shown by in vitro studies that PGE(2) signaling transactivates epidermal growth factor receptor (EGFR) through an intracellular mechanism. However, the mechanisms underlying PGE(2)-induced EGFR activation in in vivo tumors are still not fully understood. We previously constructed transgenic mice that develop gastric tumors caused by oncogenic activation and PGE(2) pathway induction. Importantly, expression of EGFR ligands, epiregulin, amphiregulin, heparin-binding EGF-like growth factor, and betacellulin, as well as a disintegrin and metalloproteinases (ADAMs), ADAM8, ADAM9, ADAM10, and ADAM17 were significantly increased in the mouse gastric tumors in a PGE(2) pathway-dependent manner. These ADAMs can activate EGFR by ectodomain shedding of EGFR ligands. Notably, the extensive induction of EGFR ligands and ADAMs was suppressed by inhibition of the PGE(2) receptor EP4. Moreover, EP4 signaling induced expression of amphiregulin and epiregulin in activated macrophages, whereas EP4 pathway was required for basal expression of epiregulin in gastric epithelial cells. In contrast, ADAMs were not induced directly by PGE(2) in these cells, suggesting indirect mechanism possibly through PGE(2)-associated inflammatory responses. These results suggest that PGE(2) signaling through EP4 activates EGFR in gastric tumors through global induction of EGFR ligands and ADAMs in several cell types either by direct or indirect mechanism. Importantly, gastric tumorigenesis of the transgenic mice was significantly suppressed by combination treatment with EGFR and COX-2 inhibitors. Therefore, it is possible that inhibition of both COX-2/PGE(2) and EGFR pathways represents an effective strategy for preventing gastric cancer.
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oshima
authors.forename: Boryana K
authors.initials: BK
authors.lastname: Popivanova
authors.forename: Keisuke
authors.initials: K
authors.lastname: Oguma
authors.forename: Dan
authors.initials: D
authors.lastname: Kong
authors.forename: Tomo-o
authors.initials: TO
authors.lastname: Ishikawa
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D066258:Amphiregulin; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D066259:Betacellulin; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism; D066255:EGF Family of Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D066258:Amphiregulin; D015703:Antigens, CD; C587849:Areg protein, mouse; D066259:Betacellulin; D014408:Biomarkers, Tumor; C587852:Btc protein, mouse; D003598:Cytoskeletal Proteins; D019483:Disintegrins; D066255:EGF Family of Proteins; D066260:Epiregulin; C587881:Ereg protein, mouse; C501171:Gan protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C545651:Ptger4 protein, mouse; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D051722:ADAM Proteins; C489402:Adam8 protein, mouse; D015232:Dinoprostone