title: Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis.
abstract: Necroptosis is a programmed form of non-apoptotic cell death that requires the kinase activity of the receptor interacting protein kinase 3 (RIPK3). Although in vitro data suggests that cancer cells lacking expression of RIPK3 are invasive, the physiological role of RIPK3 in a disease-relevant setting remains unknown. Here we provide evidence that RIPK3 has a critical role in suppressing colorectal cancer (CRC). RIPK3-deficient mice were highly susceptible to colitis-associated CRC and exhibited greater production of pro-inflammatory mediators and tumor promoting factors. Tumorigenesis in RIPK3-deficiency resulted from uncontrolled activation of NF-κB, STAT3, AKT and Wnt-β-catenin signaling pathways that enhanced the ability of intestinal epithelial cells (IECs) to aberrantly proliferate in the face of the sustained inflammatory microenvironment and promote CRC. We found that RIPK3 expression is reduced in tumors from patients with inflammatory bowel diseases, and further confirmed that expression of RIPK3 is downregulated in human CRC and correlated with cancer progression. Thus, our results reveal that the necroptosis adaptor RIPK3 has key anti-inflammatory and anti-tumoral functions in the intestine, and define RIPK3 as a novel colon tumor suppressor.
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bozec
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Alina C
authors.initials: AC
authors.lastname: Iuga
authors.affiliation: The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Gastroenterology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Roda
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Sobi, Inc., Waltham, MA 02452, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dahan
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Garabet
authors.initials: G
authors.lastname: Yeretssian
mesh_terms: D000818:Animals; D016923:Cell Death; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003092:Colitis / Q000150:complications; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: IBD-related CRC; RIPK3; colorectal cancer; necroptosis