title: Genome-wide analysis reveals downregulation of miR-379/miR-656 cluster in human cancers.
abstract: BACKGROUND
  MicroRNAs (miRNAs) are non-uniformly distributed in genomes and ~30% of the miRNAs in the human genome are clustered. In this study we have focused on the imprinted miRNA cluster miR-379/miR-656 on 14q32.31 (hereafter C14) to test their coordinated function. We have analyzed expression profile of >1000 human miRNAs in >1400 samples representing seven different human tissue types obtained from cancer patients along with matched and unmatched controls.
  
  
  RESULTS
  We found 68% of the miRNAs in this cluster to be significantly downregulated in glioblastoma multiforme (GBM), 61% downregulated in kidney renal clear cell carcinoma (KIRC), 46% in breast invasive carcinoma (BRCA) and 14% in ovarian serous cystadenocarcinoma (OV). On a genome-wide scale C14 miRNAs accounted for 12-30% of the total downregulated miRNAs in different cancers. Pathway enrichment for the predicted targets of C14 miRNA was significant for cancer pathways, especially Glioma (p< 3.77x10⁻⁶, FDR<0.005). The observed downregulation was confirmed in GBM patients by real-time PCR, where 79% of C14 miRNAs (34/43) showed downregulation. In GBM samples, hypermethylation at C14 locus (p<0.003) and downregulation of MEF2, a crucial transcription factor for the cluster was observed which likely contribute to the observed downregulation of the entire miRNA cluster.
  
  
  CONCLUSIONS
  We provide compelling evidence that the entire C14 miRNA cluster is a tumor suppressor locus involved in multiple cancers, especially in GBM, and points toward a general mechanism of coordinated function for clustered miRNAs.
authors.affiliation: CSIR-Institute of Genomics & Integrative Biology, G,N, Ramachandran Knowledge Centre for Genome Informatics, Delhi, India.
authors.forename: Saurabh V
authors.initials: SV
authors.lastname: Laddha
authors.forename: Subhashree
authors.initials: S
authors.lastname: Nayak
authors.forename: Deepanjan
authors.initials: D
authors.lastname: Paul
authors.forename: Rajasekhara
authors.initials: R
authors.lastname: Reddy
authors.forename: Charu
authors.initials: C
authors.lastname: Sharma
authors.forename: Prerana
authors.initials: P
authors.lastname: Jha
authors.forename: Manoj
authors.initials: M
authors.lastname: Hariharan
authors.forename: Anurag
authors.initials: A
authors.lastname: Agrawal
authors.forename: Shantanu
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Chitra
authors.initials: C
authors.lastname: Sarkar
authors.forename: Arijit
authors.initials: A
authors.lastname: Mukhopadhyay
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D005910:Glioma / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C561022:MIRN379 microRNA, human; D035683:MicroRNAs