Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila.
Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila.
复制标题
DOI：
10.1371/journal.ppat.1002939
复制
发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Guillemin K
中科院分区：
文献类型：
--
作者：
Wandler AM;Guillemin K
Gastric cancer development is strongly correlated with infection by Helicobacter pylori possessing the effector protein CagA. Using a transgenic Drosophila melanogaster model, we show that CagA expression in the simple model epithelium of the larval wing imaginal disc causes dramatic tissue perturbations and apoptosis when CagA-expressing and non-expressing cells are juxtaposed. This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells. We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis. In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner. These data suggest a potential role for CagA-mediated JNK pathway activation in promoting gastric cancer progression. The gastric pathogen Helicobacter pylori infects an estimated 50% of the world's population and is a major risk factor for the development of gastric cancer. Strains of H. pylori that can inject the CagA effector protein into host cells are known to be more virulent, but the potential contributions of host genetics to pathogenesis are not well-understood. Using transgenic Drosophila melanogaster, we show that the genetic context of both the host cells in which CagA is expressed and their neighboring cells changes CagA's effects on epithelial tissue. When CagA is expressed in a subset of cells within an epithelium, it disrupts tissue integrity and induces apoptosis through activation of JNK signaling, a pathway that functions to remove aberrant cells from an epithelium. CagA's proapoptotic effects are inhibited by neoplastic tumor suppressor genes in CagA-expressing cells, and by the tumor necrosis factor homolog Eiger in neighboring cells. In contrast, when CagA is coexpressed with oncogenic Ras in a Drosophila model of metastasis, it enhances the growth and invasion of tumors in a JNK-dependent manner. Our study demonstrates how changes in host genetics can cooperate with activation of JNK signaling by the bacterial virulence factor CagA to promote tumorigenesis.
登录
查看更多内容
影响因子：
6.7
作者：
Botham, Crystal M.;Wandler, Anica M.;Guillemin, Karen
通讯作者：
Guillemin, Karen
影响因子：
2.5
作者：
de Beco, Simon;Ziosi, Marcello;Johnston, Laura A.
通讯作者：
Johnston, Laura A.
影响因子：
32.4
作者：
Kasper, Christoph Alexander;Sorg, Isabel;Arrieumerlou, Cecile
通讯作者：
Arrieumerlou, Cecile
影响因子：
9.2
作者：
Igaki, Tatsushi;Pagliarini, Raymond A.;Xu, Tian
通讯作者：
Xu, Tian
影响因子：
7.2
作者：
Igaki, Tatsushi
通讯作者：
Igaki, Tatsushi