cGAS restricts colon cancer development by protecting intestinal barrier integrity

Shuiqing Hu, Yan Fang, Xiang Chen, Tianlei Cheng, Miaoqing Zhao, Mingjian Du, Tuo Li, Minghao Li, Zhiqun Zeng, Yonglong Wei, Zhimin Gu, Conggang Zhang, Lijun Sun, Zhijian J. Chen

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.

Original languageEnglish (US)
Article numbere2105747118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number23
DOIs
StatePublished - Jun 8 2021

Keywords

  • CGAS
  • Colon cancer
  • Inflammation
  • Innate immunity
  • STING

ASJC Scopus subject areas

  • General

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