title: Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis.
abstract: Loss of parietal cells initiates the development of spasmolytic polypeptide-expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) that enhances the ability to defend against reactive oxygen species (ROS) in epithelial cells is expressed de novo in SPEM of K19-Wnt1/C2mE mice, a transgenic model of gastric tumorigenesis, and is required for the efficient development of SPEM and gastric tumor in these animals. The role of ROS and its downstream signaling in CD44-dependent gastric tumorigenesis has remained unknown, however. With the use of the K19-Wnt1/C2mE mouse, we now show that parietal cells in the inflamed stomach are highly sensitive to oxidative stress and manifest activation of p38(MAPK) signaling by ROS. Oral treatment with the antioxidant ascorbic acid or genetic ablation of the Ink4a/Arf locus, a major downstream target of ROS-p38(MAPK) signaling, inhibited parietal cell loss and the subsequent gastric tumorigenesis. Our results indicate that signaling activated by oxidative stress in parietal cells plays a key role in CD44-dependent gastric tumorigenesis. .
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Ryo
authors: R
authors: Seishima
authors: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Takeyuki
authors: T
authors: Wada
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Kenji
authors: K
authors: Tsuchihashi
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Shogo
authors: S
authors: Okazaki
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Momoko
authors: M
authors: Yoshikawa
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Hiroko
authors: H
authors: Oshima
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Masanobu
authors: M
authors: Oshima
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Toshiro
authors: T
authors: Sato
authors: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Hirotoshi
authors: H
authors: Hasegawa
authors: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Yuko
authors: Y
authors: Kitagawa
authors: Nashville VA Medical Center and the Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors: James R
authors: JR
authors: Goldenring
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Hideyuki
authors: H
authors: Saya
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. osmna@sb3.so-net.ne.jp.
authors: Osamu
authors: O
authors: Nagano
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051155:Wnt1 Protein / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C476399:Cd44 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018960:Hyaluronan Receptors; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D020823:ADP-Ribosylation Factor 1