TY - JOUR
T1 - Ink4a/arf-dependent loss of parietal cells induced by oxidative stress promotes CD44-dependent gastric tumorigenesis
AU - Seishima, Ryo
AU - Wada, Takeyuki
AU - Tsuchihashi, Kenji
AU - Okazaki, Shogo
AU - Yoshikawa, Momoko
AU - Oshima, Hiroko
AU - Oshima, Masanobu
AU - Sato, Toshiro
AU - Hasegawa, Hirotoshi
AU - Kitagawa, Yuko
AU - Goldenring, James R.
AU - Saya, Hideyuki
AU - Nagano, Osamu
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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 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.
AB - 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 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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U2 - 10.1158/1940-6207.CAPR-15-0025-T
DO - 10.1158/1940-6207.CAPR-15-0025-T
M3 - Article
C2 - 25813526
AN - SCOPUS:84941781901
SN - 1940-6207
VL - 8
SP - 492
EP - 501
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 6
ER -
