Wnt信号通路
卡加
生物
细胞生物学
肠内分泌细胞
LGR5型
幽门螺杆菌
干细胞
四斯潘宁
信号转导
细胞
内分泌学
内分泌系统
激素
生物化学
毒力
遗传学
基因
作者
Atsushi Takahashi‐Kanemitsu,Mengxue Lu,Christopher T. G. Knight,Takayoshi Yamamoto,Takuo Hayashi,Yusuke Mii,Takuya Ooki,Ippei Kikuchi,Akira Kikuchi,Nick Barker,Etsuo A. Susaki,Masanori Taira,Masanori Hatakeyama
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2023-07-18
卷期号:16 (794)
被引量:5
标识
DOI:10.1126/scisignal.abp9020
摘要
Helicobacter pylori strains that deliver the oncoprotein CagA into gastric epithelial cells are the major etiologic agents of upper gastric diseases including gastric cancer. CagA promotes gastric carcinogenesis through interactions with multiple host proteins. Here, we show that CagA also disrupts Wnt-dependent planar cell polarity (Wnt/PCP), which orients cells within the plane of an epithelium and coordinates collective cell behaviors such as convergent extension to enable epithelial elongation during development. Ectopic expression of CagA in Xenopus laevis embryos impaired gastrulation, neural tube formation, and axis elongation, processes driven by convergent extension movements that depend on the Wnt/PCP pathway. Mice specifically expressing CagA in the stomach epithelium had longer pyloric glands and mislocalization of the tetraspanin proteins VANGL1 and VANGL2 (VANGL1/2), which are critical components of Wnt/PCP signaling. The increased pyloric gland length was due to hyperproliferation of cells at the gland base, where Lgr5 + stem and progenitor cells reside, and was associated with fewer differentiated enteroendocrine cells. In cultured human gastric epithelial cells, the N terminus of CagA interacted with the C-terminal cytoplasmic tails of VANGL1/2, which impaired Wnt/PCP signaling by inducing the mislocalization of VANGL1/2 from the plasma membrane to the cytoplasm. Thus, CagA may contribute to the development of gastric cancer by subverting a Wnt/PCP-dependent mechanism that restrains pyloric gland stem cell proliferation and promotes enteroendocrine differentiation.
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