The oncogenic microRNA miR-21 promotes regulated necrosis in mice

Xiaodong Ma (), Daniel J. Conklin, Fenge Li, Zhongping Dai, Xiang Hua, Yan Li, Zijun Y. Xu-Monette, Ken H. Young, Wei Xiong, Marcin Wysoczynski, Srinivas D. Sithu, Sanjay Srivastava, Aruni Bhatnagar and Yong Li ()
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Xiaodong Ma: Lerner Research Institute, Cleveland Clinic
Daniel J. Conklin: Diabetes and Obesity Center, University of Louisville
Fenge Li: Diabetes and Obesity Center, University of Louisville
Zhongping Dai: Fox Chase Cancer Center, Institute for Cancer Research
Xiang Hua: Fox Chase Cancer Center, Institute for Cancer Research
Yan Li: School of Medicine, University of Louisville
Zijun Y. Xu-Monette: MD Anderson Cancer Center
Ken H. Young: MD Anderson Cancer Center
Wei Xiong: Cancer Research Institute, Central South University
Marcin Wysoczynski: Diabetes and Obesity Center, University of Louisville
Srinivas D. Sithu: Diabetes and Obesity Center, University of Louisville
Sanjay Srivastava: Diabetes and Obesity Center, University of Louisville
Aruni Bhatnagar: Diabetes and Obesity Center, University of Louisville
Yong Li: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract MicroRNAs (miRNAs) regulate apoptosis, yet their role in regulated necrosis remains unknown. miR-21 is overexpressed in nearly all human cancer types and its role as an oncogene is suggested to largely depend on its anti-apoptotic action. Here we show that miR-21 is overexpressed in a murine model of acute pancreatitis, a pathologic condition involving RIP3-dependent regulated necrosis (necroptosis). Therefore, we investigate the role of miR-21 in acute pancreatitis injury and necroptosis. miR-21 deficiency protects against caerulein- or L-arginine-induced acute pancreatitis in mice. miR-21 inhibition using locked-nucleic-acid-modified oligonucleotide effectively reduces pancreatitis severity. miR-21 deletion is also protective in tumour necrosis factor-induced systemic inflammatory response syndrome. These data suggest that miRNAs are critical participants in necroptosis and miR-21 enhances cellular necrosis by negatively regulating tumour suppressor genes associated with the death-receptor-mediated intrinsic apoptosis pathway, and could be a therapeutic target for preventing pathologic necrosis.

Date: 2015
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DOI: 10.1038/ncomms8151

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