The Helicobacter pylori CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells.

Autor: Takahashi-Kanemitsu A; Department of Microbiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.; Department of Biochemistry and Systems Biomedicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan., Lu M; Department of Microbiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan., Knight CT; Department of Microbiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan., Yamamoto T; Department of Biological Sciences, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.; Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan., Hayashi T; Department of Human Pathology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan., Mii Y; National Institute for Basic Biology and Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.; Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama 332-0012, Japan., Ooki T; Department of Microbiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.; Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo 141-0021, Japan., Kikuchi I; Department of Microbiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.; Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo 141-0021, Japan., Kikuchi A; Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.; Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan., Barker N; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore.; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; Division of Epithelial Stem Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa 924-1192, Japan., Susaki EA; Department of Biochemistry and Systems Biomedicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan., Taira M; Department of Biological Sciences, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.; Department of Biological Sciences, Faculty of Science and Engineering, Chuo University, Bunkyo-ku, Tokyo 112-8551, Japan., Hatakeyama M; Department of Microbiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.; Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo 141-0021, Japan.; Research Center of Microbial Carcinogenesis, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2023 Jul 18; Vol. 16 (794), pp. eabp9020. Date of Electronic Publication: 2023 Jul 18.
DOI: 10.1126/scisignal.abp9020
Abstrakt: Helicobacter pylori strains that deliver the oncoprotein CagA into gastric epithelial cells are the major etiologic agents of upper gastric diseases including gastric cancer. CagA promotes gastric carcinogenesis through interactions with multiple host proteins. Here, we show that CagA also disrupts Wnt-dependent planar cell polarity (Wnt/PCP), which orients cells within the plane of an epithelium and coordinates collective cell behaviors such as convergent extension to enable epithelial elongation during development. Ectopic expression of CagA in Xenopus laevis embryos impaired gastrulation, neural tube formation, and axis elongation, processes driven by convergent extension movements that depend on the Wnt/PCP pathway. Mice specifically expressing CagA in the stomach epithelium had longer pyloric glands and mislocalization of the tetraspanin proteins VANGL1 and VANGL2 (VANGL1/2), which are critical components of Wnt/PCP signaling. The increased pyloric gland length was due to hyperproliferation of cells at the gland base, where Lgr5 + stem and progenitor cells reside, and was associated with fewer differentiated enteroendocrine cells. In cultured human gastric epithelial cells, the N terminus of CagA interacted with the C-terminal cytoplasmic tails of VANGL1/2, which impaired Wnt/PCP signaling by inducing the mislocalization of VANGL1/2 from the plasma membrane to the cytoplasm. Thus, CagA may contribute to the development of gastric cancer by subverting a Wnt/PCP-dependent mechanism that restrains pyloric gland stem cell proliferation and promotes enteroendocrine differentiation.
Databáze: MEDLINE