Ink4a/arf-dependent loss of parietal cells induced by oxidative stress promotes CD44-dependent gastric tumorigenesis

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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<sup>MAPK</sup> 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<sup>MAPK</sup> 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.

Original languageEnglish
Pages (from-to)492-501
Number of pages10
JournalCancer Prevention Research
Volume8
Issue number6
DOIs
Publication statusPublished - 2015 Jun 1

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Stomach
Carcinogenesis
Oxidative Stress
Reactive Oxygen Species
Metaplasia
Transgenic Mice
Ascorbic Acid
Antioxidants
Epithelial Cells
spasmolytic polypeptide
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ink4a/arf-dependent loss of parietal cells induced by oxidative stress promotes CD44-dependent gastric tumorigenesis. / Seishima, Ryo; Wada, Takeyuki; Tsuchihashi, Kenji; Okazaki, Shogo; Yoshikawa, Momoko; Oshima, Hiroko; Oshima, Masanobu; Sato, Toshiro; Hasegawa, Hirotoshi; Kitagawa, Yuukou; Goldenring, James R.; Saya, Hideyuki; Nagano, Osamu.

In: Cancer Prevention Research, Vol. 8, No. 6, 01.06.2015, p. 492-501.

Research output: Contribution to journalArticle

Seishima, Ryo ; Wada, Takeyuki ; Tsuchihashi, Kenji ; Okazaki, Shogo ; Yoshikawa, Momoko ; Oshima, Hiroko ; Oshima, Masanobu ; Sato, Toshiro ; Hasegawa, Hirotoshi ; Kitagawa, Yuukou ; Goldenring, James R. ; Saya, Hideyuki ; Nagano, Osamu. / Ink4a/arf-dependent loss of parietal cells induced by oxidative stress promotes CD44-dependent gastric tumorigenesis. In: Cancer Prevention Research. 2015 ; Vol. 8, No. 6. pp. 492-501.
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