title: Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis.
abstract: MicroRNA 21 (miR-21) is overexpressed in virtually all types of carcinomas and various types of hematological malignancies. To determine whether miR-21 promotes tumor development in vivo, we knocked out the miR-21 allele in mice. In response to the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate mouse skin carcinogenesis protocol, miR-21-null mice showed a significant reduction in papilloma formation compared with wild-type mice. We revealed that cellular apoptosis was elevated and cell proliferation was decreased in mice deficient of miR-21 compared to wild-type animals. In addition, we found that a large number of validated or predicted miR-21 target genes were up-regulated in miR-21-null keratinocytes, which are precursor cells to skin papillomas. Specifically, up-regulation of Spry1, Pten, and Pdcd4 when miR-21 was ablated coincided with reduced phosphorylation of ERK, AKT, and JNK, three major downstream effectors of Ras activation that plays a predominant role in DMBA-initiated skin carcinogenesis. These results provide in vivo evidence that miR-21 exerts its oncogenic function through negatively regulating its target genes.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40202, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
authors.forename: Munish
authors.initials: M
authors.lastname: Kumar
authors.forename: Saibyasachi N
authors.initials: SN
authors.lastname: Choudhury
authors.forename: Lindsey E
authors.initials: LE
authors.lastname: Becker Buscaglia
authors.forename: Juanita R
authors.initials: JR
authors.lastname: Barker
authors.forename: Keerthy
authors.initials: K
authors.lastname: Kanakamedala
authors.forename: Mo-Fang
authors.initials: MF
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002273:Carcinogens / Q000494:pharmacology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D015127:9,10-Dimethyl-1,2-benzanthracene; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate