Loss of aryl hydrocarbon receptor promotes colon tumorigenesis in ApcS580/þ; KrasG12D/þ mice

Huajun Han, Laurie A. Davidson, Martha Hensel, Grace Yoon, Kerstin Landrock, Clinton Allred, Arul Jayaraman, Ivan Ivanov, Stephen H. Safe, Robert S. Chapkin

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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/þ; KrasG12D/þ 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.

Original languageEnglish (US)
Pages (from-to)771-783
Number of pages13
JournalMolecular Cancer Research
Volume19
Issue number5
DOIs
StatePublished - May 1 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Loss of aryl hydrocarbon receptor promotes colon tumorigenesis in ApcS580/þ; KrasG12D/þ mice'. Together they form a unique fingerprint.

Cite this