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Title: Necroptosis is dispensable for the development of inflammation-associated or sporadic colon cancer in mice.
Austin Authors: Alvarez-Diaz, Silvia;Preaudet, Adele;Samson, Andre L;Nguyen, Paul M;Fung, Ka Yee;Garnham, Alexandra L;Alexander, Warren S;Strasser, Andreas;Ernst, Matthias ;Putoczki, Tracy L;Murphy, James M
Affiliation: Department of Medical Biology, University of Melbourne, Parkville, VIC, 3050, Australia..
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia..
Olivia Newton-John Cancer Research Institute
La Trobe University School of Cancer Medicine, Heidelberg, VIC, 3084, Australia..
Issue Date: May-2021
Date: 2020
Publication information: Cell death and differentiation 2021; 28(5): 1466-1476
Abstract: Chronic inflammation of the large intestine is associated with an increased risk of developing colorectal cancer (CRC), the second most common cause of cancer-related deaths worldwide. Necroptosis has emerged as a form of lytic programmed cell death that, distinct from apoptosis, triggers an inflammatory response. Dysregulation of necroptosis has been linked to multiple chronic inflammatory diseases, including inflammatory bowel disease and cancer. Here, we used murine models of acute colitis, colitis-associated CRC, sporadic CRC, and spontaneous intestinal tumorigenesis to investigate the role of necroptosis in these gastrointestinal pathologies. In the Dextran Sodium Sulfate-induced acute colitis model, in some experiments, mice lacking the terminal necroptosis effector protein, MLKL, or its activator RIPK3, exhibited greater weight loss compared to wild-type mice, consistent with some earlier reports. However, the magnitude of weight loss and accompanying inflammatory pathology upon Mlkl deletion varied substantially between independent repeats. Such variation provides a possible explanation for conflicting literature reports. Furthermore, contrary to earlier reports, we observed that genetic deletion of MLKL had no impact on colon cancer development using several mouse models. Collectively, these data do not support an obligate role for necroptosis in inflammation or cancer within the gastrointestinal tract.
DOI: 10.1038/s41418-020-00673-z
ORCID: 0000-0002-0637-2716
Journal: Cell death and differentiation
PubMed URL: 33230260
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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