Research Papers:

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

Dominique Bozec _, Alina C. Iuga, Giulia Roda, Stephanie Dahan and Garabet Yeretssian

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Oncotarget. 2016; 7:46384-46400. https://doi.org/10.18632/oncotarget.10135

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Dominique Bozec1,2, Alina C. Iuga3, Giulia Roda4,5, Stephanie Dahan1,2,6,*, Garabet Yeretssian1,2,7

1Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

2Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

3Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA

4The 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

5Gastroenterology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy

6Sobi, Inc., Waltham, MA 02452, USA

7Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

*The author changed affiliation after the course of the work and currently is employed by Sobi, Inc., but that the article in no way represents the work product, views or opinions of Sobi, Inc.

Correspondence to:

Garabet Yeretssian, email: [email protected]

Keywords: colorectal cancer, IBD-related CRC, necroptosis, RIPK3

Received: May 05, 2016    Accepted: June 03, 2016    Published: June 17, 2016


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.

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