@article{e0858c6b3d744f90b36df2bd614a9626,
title = "Loss of aryl hydrocarbon receptor promotes colon tumorigenesis in ApcS580/{\th}; KrasG12D/{\th} mice",
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 ApcS580/{\th}; KrasG12D/{\th} 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.",
author = "Huajun Han and Davidson, {Laurie A.} and Martha Hensel and Grace Yoon and Kerstin Landrock and Clinton Allred and Arul Jayaraman and Ivan Ivanov and Safe, {Stephen H.} and Chapkin, {Robert S.}",
note = "Funding Information: L.A. Davidson reports grants from NIH during the conduct of the study. K. Landrock reports grants from NIH during the conduct of the study. C. Allred reports grants from NIH during the conduct of the study. A. Jayaraman reports grants from NIH during the conduct of the study. R.S. Chapkin reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors. Funding Information: We would like to thank Kristina Hielsberg for assistance in tumor studies and Jennifer Goldsby for RNA Seq-related analyses. We also thank Hans Clevers and Eric Fearon for providing the Lgr5CreERT2 reporter and CDX2PCreERT2 mice, respectively. Funding was provided by Texas AgriLife Research, the Sid Kyle Chair Endowment, the Allen Endowed Chair in Nutrition and Chronic Disease Prevention, the Cancer Prevention Research Institute of Texas (RP160589), and the National Institutes of Health (R01-ES025713, R01-CA202697, R35-CA197707, P30-ES029067, and T32-CA090301). Publisher Copyright: 2021 American Association for Cancer Research.",
year = "2021",
month = may,
day = "1",
doi = "10.1158/1541-7786.MCR-20-0789",
language = "English (US)",
volume = "19",
pages = "771--783",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "5",
}