Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer
Shuang Tang, … , John A. Cidlowski, Xiaoling Li
Shuang Tang, … , John A. Cidlowski, Xiaoling Li
Published November 16, 2021
Citation Information: JCI Insight. 2021;6(24):e151815. https://doi.org/10.1172/jci.insight.151815.
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Research Article Gastroenterology Oncology

Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer

Abstract

Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial GC receptor (GR), but not whole intestinal tissue GR, promoted chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In patients with colorectal cancer, GR was enriched in intestinal epithelial cells and high epithelial cell GR levels were associated with poor prognosis. Consistently, intestinal epithelium–specific deletion of GR (GR iKO) in mice increased macrophage infiltration, improved tissue recovery, and enhanced antitumor response in a chronic inflammation–associated colorectal cancer model. Consequently, GR iKO mice developed fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early phase of tissue injury delayed recovery and accelerated the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling repressed acute colitis but promoted chronic inflammation–associated colorectal cancer. Our study suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that, although synthetic GC treatment for IBD should be used with caution, there is a therapeutic window for GC therapy during colorectal cancer development in immunocompetent patients.

Authors

Shuang Tang, Zhan Zhang, Robert H. Oakley, Wenling Li, Weijing He, Xiaojiang Xu, Ming Ji, Qing Xu, Liang Chen, Alicia S. Wellman, Qingguo Li, Leping Li, Jian-Liang Li, Xinxiang Li, John A. Cidlowski, Xiaoling Li

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Figure 3

Deletion of intestinal epithelial GR increases susceptibility to DSS-induced colitis in mice.

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Deletion of intestinal epithelial GR increases susceptibility to DSS-ind...
(A–E) Six-month-old Flox and GR iKO mice were treated with 2.5% DSS in drinking water for 7 days. (A) Their body weight loss, (B) the percentage of animals displaying rectal bleeding, (C) the percentages of mice by rectal bleeding severity category, (D) bloody stool positivity, and (E) the colon length were analyzed (n = 16 Flox mice and 17 GR iKO mice from two independent experiments). Data in (A and E) represent mean ± SEM, *P < 0.05, Mann-Whitney test. (F and G) H&E-stained colon sections from DSS-treated Flox and GR iKO mice were examined, and nonproliferative lesions were graded and recorded, as described in the Methods. Scale bar: 200 μm. The orange arrow denotes inflammation, the brown arrow denotes glandular atrophy and loss, the black arrow denotes fibrosis, the blue arrow denotes submucosal edema, and green arrows denote mucosal erosion. (G) Pathological scores shown with box-and-whisker plot, where whiskers represent the maximum and minimum values (n = 10 Flox mice and 8 GR iKO mice, *P < 0.05, Mann-Whitney test). (H) GR-deficient mouse colons have increased proinflammatory gene levels after DSS administration (n = 4 Flox mice administered regular water, 8 Flox mice treated with DSS, 4 GR iKO mice administered regular water, and 9 GR iKO mice treated with DSS; data represent mean ± SEM; *q < 0.05, **q < 0.01, 2-way ANOVA test).