IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3

Cancer Cell. 2016 May 9;29(5):684-696. doi: 10.1016/j.ccell.2016.03.014. Epub 2016 Apr 14.


Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment.

Keywords: IRAK-M; STAT3; Toll-like receptors; Wnt signaling; colorectal cancer; microbiome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Colitis / immunology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / microbiology*
  • Disease Progression
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / immunology*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Microbiota / immunology*
  • Phosphorylation / immunology
  • Prognosis
  • Protein Stability
  • STAT3 Transcription Factor / immunology*
  • STAT3 Transcription Factor / metabolism
  • Survival Analysis
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism
  • Wnt Signaling Pathway / immunology


  • STAT3 Transcription Factor
  • Toll-Like Receptors
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse