Wada Yuriko, Takemura Kosuke, Tummala Padmaja, Uchida Keisuke, Kitagaki Keisuke, Furukawa Asuka, Ishige Yuuki, Ito Takashi, Hara Yukichi, Suzuki Takashige, Mimuro Hitomi, Board Philip G, Eishi Yoshinobu
Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan.
Department of Urology Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Japan.
FEBS Open Bio. 2018 Mar 9;8(4):671-679. doi: 10.1002/2211-5463.12402. eCollection 2018 Apr.
Infection with is known to decrease the level of glutathione in gastric epithelial cells and increase the production of reactive oxygen species (ROS), which can lead to DNA damage and the development of gastric cancer. Cation transport regulator 1 (CHAC1) has γ-glutamylcyclotransferase activity that degrades glutathione. We found that -positive infection triggered CHAC1 overexpression in human gastric epithelial (AGS) cells leading to glutathione degradation and the accumulation of ROS. Nucleotide alterations in the tumour suppressor gene were induced in AGS cells overexpressing CHAC1, whereas no mutations were detected in cells overexpressing a catalytically inactive mutant of CHAC1. A high frequency of mutations occurred in -infected AGS cells, but this was prevented in cells transfected with CHAC1 siRNA. These findings indicate that -mediated CHAC1 overexpression degrades intracellular glutathione, allowing the accumulation of ROS which subsequently causes mutations that could contribute to the development of gastric cancer.
已知感染会降低胃上皮细胞中谷胱甘肽的水平并增加活性氧（ROS）的产生，这会导致DNA损伤和胃癌的发生。阳离子转运调节因子1（CHAC1）具有降解谷胱甘肽的γ-谷氨酰环转移酶活性。我们发现，阳性感染会触发人胃上皮（AGS）细胞中CHAC1的过表达，导致谷胱甘肽降解和ROS积累。在过表达CHAC1的AGS细胞中诱导了肿瘤抑制基因的核苷酸改变，而在过表达CHAC1催化失活突变体的细胞中未检测到突变。在感染的AGS细胞中发生了高频突变，但在用CHAC1 siRNA转染的细胞中这种情况得到了预防。这些发现表明，介导的CHAC1过表达会降解细胞内谷胱甘肽，使ROS积累，随后导致可能促成胃癌发生的突变。
