Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis.

Seishima R, Wada T, Tsuchihashi K, Okazaki S, Yoshikawa M, Oshima H, Oshima M, Sato T, Hasegawa H, Kitagawa Y, Goldenring JR, Saya H, Nagano O
Cancer Prev Res (Phila). 2015 8 (6): 492-501

PMID: 25813526 · DOI:10.1158/1940-6207.CAPR-15-0025-T

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. .

©2015 American Association for Cancer Research.

MeSH Terms (17)

ADP-Ribosylation Factor 1 Animals Cells, Cultured Cell Transformation, Neoplastic Cyclin-Dependent Kinase Inhibitor p16 Hyaluronan Receptors Immunoenzyme Techniques Metaplasia Mice Mice, Knockout Neoplastic Stem Cells Oxidative Stress p38 Mitogen-Activated Protein Kinases Parietal Cells, Gastric Signal Transduction Stomach Neoplasms Wnt1 Protein

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