RRC ID 62181
著者 Chang YJ, Wu MS, Lin JT, Chen CC.
タイトル Helicobacter pylori-Induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation.
ジャーナル J Immunol
Abstract 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.
巻・号 175(12)
ページ 8242-52
公開日 2005-12-15
DOI 10.4049/jimmunol.175.12.8242
PII 175/12/8242
PMID 16339564
MeSH Cell Line, Tumor Cyclooxygenase 2 / genetics Cyclooxygenase 2 / physiology* Dinoprostone / metabolism Helicobacter pylori* Humans Membrane Proteins / genetics Membrane Proteins / physiology* Neoplasm Invasiveness / pathology* Neovascularization, Pathologic / enzymology Neovascularization, Pathologic / virology* Promoter Regions, Genetic Stomach Neoplasms / pathology* Stomach Neoplasms / virology* Toll-Like Receptor 2 / physiology Toll-Like Receptor 9 / physiology Transcription Factor AP-1 / metabolism Transcription Factors / metabolism
IF 4.886
リソース情報
ヒト・動物細胞 MKN45(RCB1001)