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Ma X , Conklin DJ , Li F , Dai Z , Hua X , Li Y , Xu-Monette ZY , Young KH , Xiong W , Wysoczynski M , Sithu SD , Srivastava S , Bhatnagar A , Li Y
The oncogenic microRNA miR-21 promotes regulated necrosis in mice
Nat Commun. 2015 ;6 :7151
PMID: 25990308    PMCID: PMC4440243   
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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.
Ma, Xiaodong Conklin, Daniel J Li, Fenge Dai, Zhongping Hua, Xiang Li, Yan Xu-Monette, Zijun Y Young, Ken H Xiong, Wei Wysoczynski, Marcin Sithu, Srinivas D Srivastava, Sanjay Bhatnagar, Aruni Li, Yong P20 GM103492/GM/NIGMS NIH HHS/United States R01 HL055477/HL/NHLBI NIH HHS/United States England Nat Commun. 2015 May 20;6:7151. doi: 10.1038/ncomms8151.