title: Inhibition of 15-hydroxyprostaglandin dehydrogenase by Helicobacter pylori in human gastric carcinogenesis.
abstract: Helicobacter pylori (H. pylori) infection induces a chronic inflammatory response, which promotes gastric carcinogenesis. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) plays a key role as a tumor suppressor in gastrointestinal cancers. The aim of this study was to elucidate the role of 15-PGDH in gastric carcinogenesis associated with H. pylori. 15-PGDH expression in gastric biopsies from H. pylori-infected (n = 25) and noninfected (n = 15) subjects was analyzed by quantitative real-time PCR, Western blot analysis, and immunohistochemistry. 15-PGDH DNA methylation was evaluated by methylation-specific PCR and pyrosequencing. The expression of 15-PGDH, Snail, extracellular signal-regulated kinase (ERK)1/2, TLR4, and MyD88 in response to H. pylori infection was assessed by immunoblot analysis. Compared with negative specimens, H. pylori-positive specimens had 2-fold lower 15-PGDH mRNA levels and significantly less 15-PGDH protein. In four H. pylori-infected subjects with longitudinal follow-up, the suppression of 15-PGDH expression was reversed by H. pylori eradication therapy. In parallel with suppressing 15-PGDH expression, H. pylori infection activated expression of TLR4 and MyD88 expression, increased levels of phospho-ERK1/2, and increased expression of EGF receptor (EGFR)-Snail. Inhibition of Snail and MyD88 reversed suppression of 15-PGDH expression, and siMyD88 reduced phosphorylated ERK1/2. Similarly, treatment with an ERK1/2 and EGFR inhibitor also restored 15-PGDH expression. H. pylori appeared to promote gastric carcinogenesis by suppressing 15-PGDH. This process is mediated by the TLR4/MyD88 pathway via ERK1/2 or EGFR-Snail transcriptional regulation. 15-PGDH may be a useful marker and a potential therapeutic target in H. pylori-induced gastric carcinogenesis.
authors: Asan Digestive Disease Research Institute and Asan Institute for Life Sciences, Seoul, Korea.
authors: Yeon-Mi
authors: YM
authors: Ryu
authors: Seung-Jae
authors: SJ
authors: Myung
authors: Young Soo
authors: YS
authors: Park
authors: Dong-Hoon
authors: DH
authors: Yang
authors: Ho June
authors: HJ
authors: Song
authors: Jin-Yong
authors: JY
authors: Jeong
authors: Sun Mi
authors: SM
authors: Lee
authors: Miyeoun
authors: M
authors: Song
authors: Do Hoon
authors: DH
authors: Kim
authors: Hyo-Jeong
authors: HJ
authors: Lee
authors: Soo-Kyung
authors: SK
authors: Park
authors: Stephen P
authors: SP
authors: Fink
authors: Sandy D
authors: SD
authors: Markowitz
authors: Kee Wook
authors: KW
authors: Jung
authors: Kyung-Jo
authors: KJ
authors: Kim
authors: Byong Duk
authors: BD
authors: Ye
authors: Jeong-Sik
authors: JS
authors: Byeon
authors: Hwoon-Yong
authors: HY
authors: Jung
authors: Suk-Kyun
authors: SK
authors: Yang
authors: Jin-Ho
authors: JH
authors: Kim
mesh_terms: D000328:Adult; D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism; D016480:Helicobacter pylori; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000382:microbiology* / Q000473:pathology; D055815:Young Adult
chemical_list: D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase