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cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells

Oncology Research 2021年第2期29卷 87-103页

作者： BIN LIU HAIPENG LIU FEIFEI REN HANGFAN LIU IHTISHAM BUKHARI YUMING FU wanqingwu MINGHAI ZHAO SHAOGONG ZHU HUI MO FAZHAN LI MICHAEL B.ZHENG YOUCAI TANG PENGYUAN ZHENG YANG MI Henan Key Laboratory of Helicobacter Pylori&Microbiota and Gastrointestinal Cancer The Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Academy of Medical Science Zhengzhou UniversityZhengzhouChina Clinical and Translational Research Center Shanghai Pulmonary HospitalTongji University School of MedicineShanghaiChina Gastrointestinal Surgery The Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Department of Gastrointestinal Surgery Henan Cancer HospitalThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina Gastrointestinal Surgery People Hospital of Zhengzhou UniversityZhengzhouChina Faculty of Science School of Interdisciplinary ScienceHonours Life SciencesMcMaster UniversityHamiltonONCanada

The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome *** of the cyclic GMP-AMP synthase(cGAS)mediates classical DNA sensing,is involved in genome instability,and is linked to various tumor development or ***,the function of cGAS in gastric cancer remains *** this study,the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell *** employing cGAS high-expression gastric cancer cell lines,including AGS and MKN45,ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells,tumor growth,and mass in xenograft ***,database analysis predicted a possible involvement of cGAS in the DNA damage response(DDR),further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN(MRN)complex,which activated cell cycle checkpoints,even increased genome instability in gastric cancer cells,thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging ***,the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic ***,we concluded that cGAS is involved in gastric cancer progression by fueling genome instability,implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.

关键词： Gastric cancer Cell proliferation cGAS DNA damage response MRN complex

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