title: IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3.
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.
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kesselring
authors.affiliation: Institute of Microbiology and Hygiene, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Glaesner
authors.affiliation: Institute of Microbiology and Hygiene, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hiergeist
authors.affiliation: Department of Surgery, University Medical Center Erlangen, Schwabachanlage 12, 91054 Erlangen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.affiliation: Department of Internal Medicine, University Medical Center Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Neumann
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Brunner
authors.affiliation: Clinic of Gynecology and Obstetrics, Caritas Hospital St. Josef, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Wege
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Seebauer
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Köhl
authors.affiliation: Department of Surgery, University Medical Center Erlangen, Schwabachanlage 12, 91054 Erlangen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Merkl
authors.affiliation: Department of Surgery, University Medical Center Erlangen, Schwabachanlage 12, 91054 Erlangen, Germany.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Croner
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hackl
authors.affiliation: Department of Surgery, University Medical Center Erlangen, Schwabachanlage 12, 91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
authors.affiliation: Department of Internal Medicine, University Medical Center Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Institute of Microbiology and Hygiene, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Gessner
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Schlitt
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: stefan.fichtner@ukr.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fichtner-Feigl
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D018450:Disease Progression; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D064307:Microbiota / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D011379:Prognosis; D055550:Protein Stability; D050796:STAT3 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000276:immunology
chemical_list: D050796:STAT3 Transcription Factor; D051193:Toll-Like Receptors; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse
keywords: IRAK-M; STAT3; Toll-like receptors; Wnt signaling; colorectal cancer; microbiome