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Published on: October 6, 2014
Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in Apc Mice
Huajun Han1,2, Laurie A Davidson1,3, Martha Hensel4
1Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas.
Abstract:
The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of "cooperation response genes" to modulate the function of cancer "driver" genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell-targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring Apc mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis. IMPLICATIONS: Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.
Insights
Aryl hydrocarbon receptor (AhR) loss in the gut promotes colon cancer by upregulating Wnt signaling. AhR signaling suppresses Wnt, indicating its potential as a therapeutic target for colon cancer prevention and treatment.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- The genetic drivers of colorectal cancer are known, but how other genes influence them is unclear.
- The aryl hydrocarbon receptor (AhR) is a transcription factor with an unknown role in colon cancer progression.
Purpose of the Study:
- To investigate the role of AhR in modulating oncogenic signaling pathways in the colon.
- To determine if AhR influences colon stem/progenitor cell function and tumorigenesis.
Main Methods:
- Targeted knockout of AhR in intestinal epithelial cells of mice.
- Analysis of Wnt signaling pathway activation and colon stem/progenitor cell expansion.
- Assessment of mouse survival, proliferation, and tumor development in the cecum and colon.
Main Results:
- AhR knockout in intestinal epithelial cells promoted colonic stem/progenitor cell expansion and Wnt signaling.
- Loss of AhR increased cell proliferation, reduced survival, and enhanced colon tumorigenesis in mice.
- Blocking Wnt signaling with Lgr5 partially reversed the pro-tumorigenic effects of AhR loss.
Conclusions:
- AhR signaling plays a protective role in colon tumorigenesis by suppressing Wnt signaling.
- Targeting AhR may offer a novel strategy for colon cancer prevention and treatment.
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