Article Publish Status: FREE
Abstract Title:

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

Abstract Source:

Cancer Prev Res (Phila). 2015 Mar 26. Epub 2015 Mar 26. PMID: 25813526

Abstract Author(s):

Ryo Seishima, Takeyuki Wada, Kenji Tsuchihashi, Shogo Okazaki, Momoko Yoshikawa, Hiroko Oshima, Masanobu Oshima, Toshiro Sato, Hirotoshi Hasegawa, Yuko Kitagawa, James R Goldenring, Hideyuki Saya, Osamu Nagano

Article Affiliation:

Ryo Seishima


Loss of parietal cells initiates the development of spasmolytic polypeptide-expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) which 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 p38MAPK signaling by ROS. Oral treatment with the antioxidant ascorbic acid or genetic ablation of the Ink4a/Arf locus, a major downstream target of ROS-p38MAPK 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.

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