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

BIN LIU1,2,#, HAIPENG LIU3,#, FEIFEI REN1,2, HANGFAN LIU1, IHTISHAM BUKHARI1, YUMING FU4, WANQING WU4, MINGHAI ZHAO5, SHAOGONG ZHU6, HUI MO1, FAZHAN LI1,2, MICHAEL B. ZHENG7, YOUCAI TANG1,2, PENGYUAN ZHENG1,2,*, YANG MI1,2,*

1 Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
2 Academy of Medical Science, Zhengzhou University, Zhengzhou, China
3 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
4 Gastrointestinal Surgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
5 Department of Gastrointestinal Surgery, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
6 Gastrointestinal Surgery, People Hospital of Zhengzhou University, Zhengzhou, China
7 Faculty of Science, School of Interdisciplinary Science, Honours Life Sciences, McMaster University, Hamilton, ON, Canada

* Corresponding Authors: Pengyuan Zheng, email; Yang Mi, email
# These authors have contributed equally to this work and share the first authorship

Oncology Research 2021, 29(2), 87-103. https://doi.org/10.32604/or.2022.03529

Abstract

The activation of some oncogenes promote cancer cell proliferation and growth, facilitate cancer progression and 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 or therapy. However, the function of cGAS in gastric cancer remains elusive. In this study, the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines. By 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 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 contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents. Furthermore, the upregulation of 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, implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.

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Cite This Article

LIU, B., LIU, H., REN, F., LIU, H., BUKHARI, I. et al. (2021). cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells. Oncology Research, 29(2), 87–103.



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