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 1

High intestinal epithelial GR expression is associated with poor prognosis in patients with colorectal cancer.

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High intestinal epithelial GR expression is associated with poor prognos...
(A) Representative GR protein IHC images of paired colorectal cancer tissue and adjacent tissues. The levels of GR protein in a colorectal cancer tissue microarray from the Fudan University Shanghai Cancer Center were determined by immunohistochemical staining with an anti-GR antibody, as described in the Methods. Scale bar: 50 μm (second and fourth column); 200 μm (first and third column). (B) GR is highly expressed in epithelial cells in colorectal cancer tissue compared with adjacent noncancer tissue. The GR protein staining intensity in epithelial cells was scored in 431 cancer tissues and 347 adjacent tissues, as described in the Methods (data represent mean ± SEM; **** P < 0.0001, Mann-Whitney test). (C) Representative images showing high and low epithelial GR staining in the tissue microarray and the survival data of the corresponding patients. The patients included in the microarray were stratified by dichotomizing the GR expression status in cancer tissues on a continuous H-score scale of 0–300, with a cut point of 230 (n = 109 for low expression and 105 for high expression). (D) Patients with colorectal cancer with high epithelial GR expression have significantly reduced overall survival and disease-free survival. Kaplan-Meier survival analysis was performed. (E and F) Patients with colorectal cancer with high epithelial GR expression (epithelial GR high) have significantly increased hazard ratios for death and recurrence. Patients with colorectal cancer without lymph node (LN) metastasis were used as a reference to calculate the hazard ratio of patients with LN metastasis for death or recurrence. Patients with colorectal cancer with low epithelial GR expression were used as the reference to calculate the hazard ratios for death or recurrence of the patients with high epithelial GR expression.