| Abstract: | The activation of some oncogenes promote cancer cell proliferation and growth, facilitate cancer progressionand metastasis by induce DNA replication stress, even genome instability. Activation of the cyclic GMP-AMP synthase(cGAS) mediates classical DNA sensing, is involved in genome instability, and is linked to various tumor development ortherapy. However, the function of cGAS in gastric cancer remains elusive. In this study, the TCGA database andretrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues andcell lines. By employing cGAS high-expression gastric cancer cell lines, including AGS and MKN45, ectopic silencingof cGAS caused a significant reduction in the proliferation of the cells, tumor growth, and mass in xenograft mice.Mechanistically, 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 contributingto gastric cancer progression and sensitivity to treatment with DNA damaging agents. Furthermore, the upregulationof cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes.Therefore, we concluded that cGAS is involved in gastric cancer progression by fueling genome instability, implyingthat intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer. |
