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

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

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

Rebecca Kesselring et al. Cancer Cell. .

Abstract

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.

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