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Oncotarget. 2016 Jul 19;7(29):46384-46400. doi: 10.18632/oncotarget.10135.

Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis.

Bozec D1,2, Iuga AC3, Roda G4,5, Dahan S1,2,6, Yeretssian G1,2,7.

Author information

1
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
4
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.
5
Gastroenterology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.
6
Sobi, Inc., Waltham, MA 02452, USA.
7
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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.

KEYWORDS:

IBD-related CRC; RIPK3; colorectal cancer; necroptosis

PMID:
27344176
PMCID:
PMC5216805
DOI:
10.18632/oncotarget.10135
[Indexed for MEDLINE]
Free PMC Article

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