Helicobacter pylori-Induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation.
Cyclooxygenase-2 (COX-2) plays a crucial role in Helicobacter pylori-associated gastric cancer. In this study, we report that H. pylori-induced COX-2 expression enhances the cancer cell invasion and angiogenesis via TLR2 and TLR9, which can be attenuated by the specific COX-2 inhibitor NS398 or celecoxib. The cAMP response element (CRE) and AP1 sites, but not kappaB on the COX-2 promoter, are involved in MAPKs-regulated COX-2 expression. Differential bindings of the CREB-1, ATF-2, c-jun to the CRE site, and the c-fos, c-jun, ATF-2 to the AP1 site are demonstrated by DNA affinity protein-binding, supershift, and chromatin immunoprecipitation assays. Activations of these transcription factors were attenuated by different MAPKs inhibitors. The mutants of TLR2, TLR9, or MAPKs inhibited H. pylori-induced COX-2 promoter, CRE, and AP-1 activities. MAPKs inhibitors attenuated the H. pylori-induced COX-2 mRNA and protein expressions. These results indicate that H. pylori acts through TLR2 and TLR9 to activate MAPKs, especially p38, and their downstream transcription factors (CREB-1, ATF-2, c-jun, and c-fos), resulting in the activations of CRE and AP-1 on the COX-2 promoter. These intracellular networks drive the COX-2-dependent PGE2 release and contribute to cell invasion and angiogenesis.
Chang
Ya-Jen
YJ
Department of Pharmacology, National Taiwan University, Taipei, Taiwan.
Wu
Ming-Shiang
MS
Lin
Jaw-Town
JT
Chen
Ching-Chow
CC
D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism; D016480:Helicobacter pylori; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000821:virology*; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000473:pathology* / Q000821:virology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D008565:Membrane Proteins; C495342:TLR2 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone