| dc.description.abstract | The aryl hydrocarbon receptor (AhR) is a ligand-activated basic helix-loop-helix transcription factor that binds and senses cues from promiscuous ligands including environmental toxicants and dietary/microbiota-derived physiologically relevant compounds. Emerging studies have indicated that AhR plays a suppressive role in colorectal cancer (CRC) tumorigenesis, the second leading cause of cancer death in the United States. However, mechanistic insights into how AhR activation prevents colon tumorigenesis are ill-defined. Since dysregulation in colonic stem cells is generally assumed to be the most efficient sequelae of tumorigenesis, it is important to define the role of AhR signaling in the regulation of colonic stem cells.
Here, we observed that the inducible deletion of AhR in Lgr5+ stem cells increased the percentage of colonic stem cells and enhanced organoid initiating capacity and growth of both sorted stem and progenitor cells. Furthermore, intestinal specific AhR KO increased cell proliferation, and promoted colon tumorigenesis in a preclinical colitis-associated tumor model by upregulating FoxM1 signaling. Moreover, to further characterize the effect of AhR signaling on human colon adenoma transition, mice carrying ApcS580/+; KrasG12D/+ mutations, the most common mutations in CRC, were utilized. The combination of mutations in Apc, Kras, and AhR (triple mutant) increased organoid forming efficiency and growth of colonic stem/progenitor cells, and accelerated cell proliferation compared with the controls harboring only Apc and Kras mutations (double mutant). Importantly, the triple mutant organoids can grow independently of Wnt3a, R-Spondin1 and EGF growth factors by upregulating Wnt and EGF signaling and loss of AhR promoted cecum and colon tumorigenesis. Finally, AhR deficiency desensitized the response of colonic stem/progenitor cells to IL-22 signaling by upregulating expression of SOCS3, a negative regulator of IL-22 signaling, and this resulted in an impaired DNA damage repair response. Deletion of SOCS3 in AhR KO organoids restored the effect of IL-22 treatment on the DNA damage repair response pathway.
In summary, our findings indicate that AhR plays a crucial role in colon tumorigenesis by modulating colonic stem/progenitor cell behavior and provide a rationale for targeting AhR as a new potential therapeutic strategy to prevent and treat colon cancer. | en |
