Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer
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, promo...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-12-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.151815 |
| _version_ | 1811334834186878976 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shuang Tang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:15:02Z |
| format | Article |
| id | doaj.art-d06457a96cc14c058b9364939e139e71 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T17:15:02Z |
| publishDate | 2021-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d06457a96cc14c058b9364939e139e712022-12-22T02:38:09ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-12-01624Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancerShuang TangZhan ZhangRobert H. OakleyWenling LiWeijing HeXiaojiang XuMing JiQing XuLiang ChenAlicia S. WellmanQingguo LiLeping LiJian-Liang LiXinxiang LiJohn A. CidlowskiXiaoling LiSynthetic 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.https://doi.org/10.1172/jci.insight.151815GastroenterologyOncology |
| spellingShingle | 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 Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer JCI Insight Gastroenterology Oncology |
| title | Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer |
| title_full | Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer |
| title_fullStr | Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer |
| title_full_unstemmed | Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer |
| title_short | Intestinal epithelial glucocorticoid receptor promotes chronic inflammation–associated colorectal cancer |
| title_sort | intestinal epithelial glucocorticoid receptor promotes chronic inflammation associated colorectal cancer |
| topic | Gastroenterology Oncology |
| url | https://doi.org/10.1172/jci.insight.151815 |
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