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cGAS restricts colon cancer development by protecting intestinal barrier integrity

Shuiqing Hu1,2, Yan Fang1,2, Xiang Chen1,2,3

  • 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Proceedings of the National Academy of Sciences of the United States of America
|June 2, 2021
PubMed

Insights

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) protects against colon cancer. Loss of cGAS worsens inflammation and intestinal stem cell damage, increasing susceptibility to colitis-associated colon cancer.

Area of Science:

  • Immunology
  • Gastroenterology
  • Cancer Biology

Background:

  • Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a DNA-sensing enzyme crucial for immune responses.
  • Its role in endogenous tumor development, particularly in the colon, is largely unexplored.
  • Previous studies highlighted cGAS's antitumor effects in transplanted tumor models.

Purpose of the Study:

  • To investigate the role of cGAS in chemical-induced colitis and colitis-associated colon cancer (CAC) in mice.
  • To compare the susceptibility to CAC in mice lacking cGAS, STING, or type I interferon receptor.
  • To elucidate the mechanisms by which cGAS influences intestinal stem cells and barrier integrity during CAC.

Main Methods:

  • Chemical induction of colitis and CAC in wild-type and cGAS-deficient mice.
  • Assessment of susceptibility to CAC in mice lacking cGAS, STING, or type I interferon receptor.
  • Analysis of intestinal stem cell populations, barrier integrity, inflammatory markers, and immune cell profiles (STAT3, Th17, IL-10, MDSCs).

Main Results:

  • Deletion of cGAS exacerbated chemical-induced colitis and CAC development.
  • Mice lacking cGAS were more susceptible to CAC than those lacking STING or type I interferon receptor.
  • cGAS deficiency led to intestinal stem cell loss, compromised barrier integrity, increased inflammation, STAT3 activation, and altered immune cell populations (increased MDSCs and Th17, decreased IL-10).

Conclusions:

  • cGAS plays a critical protective role in controlling colitis-associated colon cancer development.
  • cGAS is essential for maintaining intestinal stem cell function and mucosal barrier integrity.
  • The findings highlight cGAS as a key regulator in the context of inflammatory bowel disease and associated tumorigenesis.
Keywords:
STINGcGAScolon cancerinflammationinnate immunity

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