p27kip1 regulates the apoptotic response of gastric epithelial cells to Helicobacter pylori
p27kip1 regulates the apoptotic response of gastric epithelial cells to Helicobacter pylori
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DOI：
10.1136/gut.2003.032144
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发表时间：
2004-06-01
期刊：
影响因子：
24.5
通讯作者：
Moss, SF
中科院分区：
文献类型：
--
作者：
Eguchi, H;Carpentier, S;Moss, SF
背景：幽门螺杆菌感染会增加患胃癌的风险，但其分子机制尚不清楚。体外长期暴露于幽门螺杆菌的胃癌细胞对细胞凋亡产生抵抗力，与低水平的p27（一种细胞周期蛋白依赖性激酶抑制剂）和在胃癌中下调的单倍体不足抑癌基因有关。目的：确定低水平的p27蛋白是否与胃癌细胞的抵抗细胞凋亡有关。方法：通过将编码全长p27 mRNA的质粒瞬时稳定转染至抗凋亡胃癌细胞中，检测增加p27蛋白表达的效果。结果：抗凋亡衍生细胞系中 p27 表达低，与 p27 mRNA 约 30% 减少和 p27 蛋白减少 80% 相关，这并不是由于 p27 蛋白的蛋白酶体依赖性降解增加所致。用 p27 构建体瞬时或稳定转染部分恢复了凋亡抗性细胞对 5-氟尿嘧啶和幽门螺杆菌诱导的细胞凋亡的敏感性，而不改变自发性凋亡细胞死亡。 结论：这些结果表明，p27 至少部分地积极调节胃上皮细胞对幽门螺杆菌的凋亡反应。胃 p27 水平低可能通过抑制细胞凋亡途径促进与幽门螺杆菌感染相关的胃癌发生。
Background: Helicobacter pylori infection increases the risk of gastric cancer but the molecular mechanisms responsible are not well understood. Gastric cells chronically exposed to H pylori in vitro develop resistance to apoptosis associated with low levels of p27, a cyclin dependent kinase inhibitor and haplo insufficient tumour suppressor gene that is downregulated in gastric cancer.Aim: To determine whether the low level of p27 protein is responsible for the resistance to apoptosis of gastric cancer cells.Methods: The effects of increasing the expression of p27 protein were examined by transiently and stably transfecting a plasmid encoding full length p27 mRNA into apoptosis resistant gastric cancer cell lines with low p27 expression that were derived from AGS gastric cancer cells by chronic H pylori coculture followed by dilutional cloning.Results: Low p27 expression in the apoptosis resistant derivative cell lines was associated with an approximate 30% decrease in p27 mRNA and an 80% decrease in p27 protein that was not due to increased proteasome dependent degradation of p27 protein. Transient or stable transfection with p27 constructs partially restored the sensitivity of the apoptosis resistant cells to 5-fluorouracil and H pylori induced apoptosis without altering spontaneous apoptotic cell death.Conclusions: These results demonstrate that p27 positively regulates, at least in part, the apoptotic response of gastric epithelial cells to H pylori. Low gastric p27 may promote gastric carcinogenesis associated with H pylori infection by inhibiting apoptotic pathways.