Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis
Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis
复制标题
氧化应激诱导的 Ink4a/Arf 依赖性壁细胞损失促进 CD44 依赖性胃肿瘤发生
作者：
R. Seishima;T. Wada;K. Tsuchihashi;S. Okazaki;Momoko Yoshikawa;H. Oshima;M. Oshima;Toshiro Sato;H. Hasegawa;Y. Kitagawa;J. Goldenring;H. Saya;O. Nagano
壁细胞的丧失启动了痉挛多肽表达化生(SPEM)的发展，SPEM是胃的一种癌前病变。CD44变异体(CD44v)在K19-WNT1/C2mE小鼠的SPEM中从头表达，CD44变异体(CD44v)增强上皮细胞抵抗ROS的能力，是这些动物SPEM和胃肿瘤有效发展所必需的。然而，ROS及其下游信号在CD44依赖的胃肿瘤发生中的作用尚不清楚。随着K19-WNT1/C2mE小鼠的使用，我们现在证明了炎症胃中的壁细胞对氧化应激高度敏感，并表明ROS激活了p38MAPK信号。口服抗氧化剂抗坏血酸或基因切除ROS-p38MAPK信号的主要下游靶点Ink4a/Arf基因座，可以抑制壁细胞丢失和随后的胃肿瘤发生。我们的结果表明，由氧化应激激活的壁细胞中的信号在CD44依赖的胃肿瘤发生中起关键作用。《癌症展望》；8(6)；492-501。©2015年AACR。
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. Cancer Prev Res; 8(6); 492–501. ©2015 AACR.
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影响因子：
29.4
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Raghothama, KG
DOI：
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发表时间：
2013
期刊：
--
影响因子：
--
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Goldenring, James R.
影响因子：
29.4
作者：
Nam KT;Lee HJ;Sousa JF;Weis VG;O'Neal RL;Finke PE;Romero-Gallo J;Shi G;Mills JC;Peek RM Jr;Konieczny SF;Goldenring JR
通讯作者：
Goldenring JR