title: The oncogenic microRNA miR-21 promotes regulated necrosis in mice.
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.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.|Institute of Pharmaceutical Research, South China Normal University, Guangzhou 510631, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, 580 South Preston Street, Delia Baxter, Louisville, Kentucky 40202, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Conklin
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, 580 South Preston Street, Delia Baxter, Louisville, Kentucky 40202, USA.
authors.forename: Fenge
authors.initials: F
authors.lastname: Li
authors.affiliation: Fox Chase Cancer Center, Institute for Cancer Research, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Fox Chase Cancer Center, Institute for Cancer Research, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Hua
authors.affiliation: Department of Surgery, School of Medicine, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.affiliation: Cancer Research Institute, Central South University, Changsha 410078, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, 580 South Preston Street, Delia Baxter, Louisville, Kentucky 40202, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wysoczynski
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, 580 South Preston Street, Delia Baxter, Louisville, Kentucky 40202, USA.
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Sithu
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, 580 South Preston Street, Delia Baxter, Louisville, Kentucky 40202, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, 580 South Preston Street, Delia Baxter, Louisville, Kentucky 40202, USA.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000235:genetics; D016026:Bone Marrow Transplantation; D020169:Caspases / Q000378:metabolism; D002108:Ceruletide / Q000235:genetics; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D007093:Imidazoles / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009336:Necrosis; D009841:Oligonucleotides / Q000235:genetics; D010195:Pancreatitis / Q000378:metabolism; D034622:RNA Interference; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D007093:Imidazoles; D007211:Indoles; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C507699:necrostatin-1; D002108:Ceruletide; D001120:Arginine; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D020169:Caspases