title: Ionizing radiation-inducible miR-27b suppresses leukemia proliferation via targeting cyclin A2.
abstract: OBJECTIVE
  Ionizing radiation is a common carcinogen that is important for the development of leukemia. However, the underlying epigenetic mechanisms remain largely unknown. The goal of the study was to explore microRNAome alterations induced by ionizing radiation (IR) in murine thymus, and to determine the role of IR-inducible microRNA (miRNA/miR) in the development of leukemia.
  
  
  METHODS
  We used the well-established C57BL/6 mouse model and miRNA microarray profiling to identify miRNAs that are differentially expressed in murine thymus in response to irradiation. TIB152 human leukemia cell line was used to determine the role of estrogen receptor-α (ERα) in miR-27b transcription. The biological effects of ectopic miR-27b on leukemogenesis were measured by western immunoblotting, cell viability, apoptosis, and cell cycle analyses.
  
  
  RESULTS
  Here, we have shown that IR triggers the differential expression of miR-27b in murine thymus tissue in a dose-, time- and sex-dependent manner. miR-27b was significantly down-regulated in leukemia cell lines CCL119 and TIB152. Interestingly, ERα was overexpressed in those 2 cell lines, and it was inversely correlated with miR-27b expression. Therefore, we used TIB152 as a model system to determine the role of ERα in miR-27b expression and the contribution of miR-27b to leukemogenesis. β-Estradiol caused a rapid and transient reduction in miR-27b expression reversed by either ERα-neutralizing antibody or ERK1/2 inhibitor. Ectopic expression of miR-27b remarkably suppressed TIB152 cell proliferation, at least in part, by inducing S-phase arrest. In addition, it attenuated the expression of cyclin A2, although it had no effect on the levels of PCNA, PPARγ, CDK2, p21, p27, p-p53, and cleaved caspase-3.
  
  
  CONCLUSIONS
  Our data reveal that β-estradiol/ERα signaling may contribute to the down-regulation of miR-27b in acute leukemia cell lines through the ERK1/2 pathway, and that miR-27b may function as a tumor suppressor that inhibits cell proliferation by targeting cyclin A2.
authors: Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada.
authors: Bo
authors: B
authors: Wang
authors: Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada.
authors: Dongping
authors: D
authors: Li
authors: Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada.
authors: Anna
authors: A
authors: Kovalchuk
authors: Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada.
authors: Dmitry
authors: D
authors: Litvinov
authors: Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada. Electronic address: olga.kovalchuk@uleth.ca.
authors: Olga
authors: O
authors: Kovalchuk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056751:Cyclin A2 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D007953:Leukemia, Radiation-Induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints; D012737:Sex Factors; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D013997:Time Factors
chemical_list: D056751:Cyclin A2; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D011960:Receptors, Estrogen; D004958:Estradiol