title: Mutual reinforcement of inflammation and carcinogenesis by the Helicobacter pylori CagA oncoprotein.
abstract: Helicobacter pylori cagA-positive strain delivers the CagA oncoprotein into gastric epithelial cells and at the same time elicits stomach inflammation. To experimentally investigate the pathophysiological interplay between CagA and inflammation, transgenic mice systemically expressing the bacterial cagA gene were treated with a colitis inducer, dextran sulfate sodium (DSS). Compared with control mice, DSS-induced colitis was markedly deteriorated in cagA-transgenic mice. In the colonic epithelia of cagA-transgenic mice, there was a substantial decrease in the level of IκB, which binds and sequesters NF-κB in the cytoplasm. This IκB reduction was due to CagA-mediated inhibition of PAR1, which may stimulate IκB degradation by perturbing microtubule stability. Whereas the CagA-mediated IκB reduction did not automatically activate NF-κB, it lowered the threshold of NF-κB activation by inflammogenic insults, thereby contributing to colitis exacerbation in cagA-transgenic mice. CagA also activates inflammasomes independently of NF-κB signaling, which further potentiates inflammation. The incidence of colonic dysplasia was elevated in DSS-treated cagA-transgenic mice due to a robust increase in the number of pre-cancerous flat-type dysplasias. Thus, CagA deteriorated inflammation, whereas inflammation strengthened the oncogenic potential of CagA. This work revealed that H. pylori CagA and inflammation reinforce each other in creating a downward spiral that instigates neoplastic transformation.
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobumi
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Murata-Kamiya
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yanagiya
authors.affiliation: Center for Omics and Bioinformatics, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Suda
authors.affiliation: Center for Omics and Bioinformatics, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Masahira
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Bingo
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Gastroenterology Division, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D063646:Carcinogenesis / Q000187:drug effects / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016264:Dextran Sulfate; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000139:chemically induced / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D058847:Inflammasomes; C080866:cagA protein, Helicobacter pylori; D016264:Dextran Sulfate