| RRC ID |
87177
|
| 著者 |
Takahashi-Kanemitsu A, Lu M, Knight CT, Yamamoto T, Hayashi T, Mii Y, Ooki T, Kikuchi I, Kikuchi A, Barker N, Susaki EA, Taira M, Hatakeyama M.
|
| タイトル |
The Helicobacter pylori CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells.
|
| ジャーナル |
Sci Signal
|
| Abstract |
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.
|
| 巻・号 |
16(794)
|
| ページ |
eabp9020
|
| 公開日 |
2023-7-18
|
| DOI |
10.1126/scisignal.abp9020
|
| PMID |
37463245
|
| MeSH |
Animals
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Carrier Proteins / metabolism
Cell Polarity
Gastric Mucosa / metabolism
Helicobacter pylori* / metabolism
Humans
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Oncogene Proteins / metabolism
Stomach Neoplasms* / genetics
|
| IF |
6.467
|
| リソース情報 |
| 実験動物マウス |
RBRC01828 |
