title: Selective activation of miRNAs of the primate-specific chromosome 19 miRNA cluster (C19MC) in cancer and stem cells and possible contribution to regulation of apoptosis.
abstract: BACKGROUND
  The human chromosome 19 miRNA cluster (C19MC) of 43 genes is a primate-specific miRNA cluster that may have biological significance in the genetic complexity of the primate. Despite previous reports on individual C19MC miRNA expression in cancer and stem cells, systematic studies on C19MC miRNA expression and biological functions are lacking.
  
  
  RESULTS
  Cluster-wide C19MC miRNA expression profiling by microarray analysis showed wholesome C19MC activation in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, in multipotent adipose-derived mesenchymal stem cells (MSCs) and a unipotent human white pre-adipocyte cell line, only selected C19MC miRNAs were expressed. MiRNA copy number analysis also showed selective C19MC expression in cancer cells with expression patterns highly similar to those in MSCs, suggesting similar miRNA regulatory mechanisms in these cells. Selective miRNA expression also suggests complex transcriptional mechanism(s) regulating C19MC expression under specific cellular and pathological conditions. Bioinformatics analysis showed that sixteen of the C19MC miRNAs share the same "AAGUGC" seed sequence with members of the miR-302/-372 family, which are known cellular reprogramming factors. In particular, C19MC-AAGUGC-miRNAs with the nucleotides 2-7 canonical seed position as in miR-302/-372 miRNAs, may play similar roles as miR-302/-372 in induced pluripotency. A biased 3p-arm selection of the C19MC-AAGUGC-miRNAs was observed indicating that targets of the 3p species of these miRNAs may be biologically significant in regulating stemness. Furthermore, bioinformatics analysis of the putative targets of the C19MC-AAGUGC-miRNAs predicted significant involvement of signaling pathways in reprogramming, many of which contribute to promoting apoptosis by indirect activation of the pro-apoptotic proteins BAK/BAX via suppression of genes of the cell survival pathways, or by enhancing caspase-8 activation through targeting inhibitors of TRAIL-inducing apoptosis.
  
  
  CONCLUSIONS
  This work demonstrated selective C19MC expression in MSCs and cancer cells, and, through miRNA profiling and bioinformatics analysis, predicted C19MC modulation of apoptosis in induced pluripotency and tumorigenesis.
authors.affiliation: Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia.|Postgraduate Program, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia.
authors.forename: Phan Nguyen Nhi
authors.initials: PN
authors.lastname: Nguyen
authors.affiliation: Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia.|Department of Animal Science & Graduate Institute of Biotechnology, Chinese Culture University, Taipei, Taiwan.
authors.forename: Chiu-Jung
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Singapore BioImaging Consortium, A*Star, Singapore, Singapore.|Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugii
authors.affiliation: Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia.|Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia.
authors.forename: Soon Keng
authors.initials: SK
authors.lastname: Cheong
authors.affiliation: Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia. chookb@utar.edu.my.|Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Center for Stem Cell Research, Universiti Tunku Abdul Rahman, Sungai Long campus, Bandar Sungai Long, Cheras, 43000, Kajang, Selangor Darul Ehsan, Malaysia. chookb@utar.edu.my.
authors.forename: Kong Bung
authors.identifier: http://orcid.org/0000-0002-0880-7867
authors.initials: KB
authors.lastname: Choo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D005810:Multigene Family; D009369:Neoplasms / Q000235:genetics*; D011323:Primates / Q000235:genetics
chemical_list: D035683:MicroRNAs
keywords: Apoptosis; C19MC; Cancer; Stem cells; miRNA expression