Reactive Oxygen Species-Induced Autophagic Degradation of Helicobacter pylori CagA Is Specifically Suppressed in Cancer Stem-like Cells

Cell Host & Microbe 12, 764-777, December 13, 2012.

Speaker: Yu-Chi Ho (賀聿齊)                                       Time: 13:10~14:00, May 15, 2013

Commentator: Dr. Jiunn-Jong Wu (吳俊忠 老師)   Place: Room 601

Abstract

Infection with strains of Helicobacter pylori that express the cytotoxin-associated antigen A (CagA), a type IV secretion effector, is associated with gastric carcinoma. It has been reported that the transfer of H. pylori-derived CagA to epithelial cells through a bacterial type IV secretion system promoted gastric carcinogenesis [1]. In addition, the systemic expression of CagA in cagA-transgenic mice induced gastrointestinal malignancies [2], revealing the oncogenic potential of CagA in mammals. However, it was also reported that CagA does not persist for a long period after H. pylori infection. In these reports, it was mentioned that autophagy was induced in gastric epithelial cells infected by H. pylori [3]. In this study, the authors further observed that CagA was degraded by autophagy after translocation into cells. The intracellular CagA degradation was induced by theH. pylori vacuolating cytotoxin, VacA, which caused the accumulation of reactive oxygen species (ROS) via decreasing the intracellular glutathione (GSH) levels and, consequently, induction of autophagy. But, how was gastric carcinogenesis triggered if CagA was degraded? They hypothesized that if CagA indeed trigger the gastric carcinogenesis, it should be transferred to slow-cycling master-regulator cells, such as the stem cells, in which autophagy is suppressed so that CagA can accumulate. It has been previously shown that CD44 is a cell surface marker related to the cancer stem cells in various tumors. Further, the gastric cancer cells expressing CD44v9, an isoform of CD44, are resistant to ROS by increasing cellular GSH level through promoting the xCT-mediated cystine uptake [4]. The authors thus examined whether the intracellular CagA escaped from autophagy and accumulated in the gastric cancer stem-like cells, which expresses CD44v9. They found CagA specifically accumulated and autophagy was repressed in these cells. These data suggest a link between H. pylori infection and gastric carcinogenesis.

References:

1. Hatakeyama, M. (2004). Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat. Rev. Cancer 4, 688–694.

2. Ohnishi, N. et al. (2008). Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc. Natl. Acad. Sci. USA 105, 1003–1008.

3. Terebiznik et al. (2009). Effect of Helicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy 5, 370–379.

4. Ishimoto et al. (2011). CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 19, 387–400.