title: Identifying microRNA/mRNA dysregulations in ovarian cancer.
abstract: BACKGROUND
  MicroRNAs are a class of noncoding RNA molecules that co-regulate the expression of multiple genes via mRNA transcript degradation or translation inhibition. Since they often target entire pathways, they may be better drug targets than genes or proteins. MicroRNAs are known to be dysregulated in many tumours and associated with aggressive or poor prognosis phenotypes. Since they regulate mRNA in a tissue specific manner, their functional mRNA targets are poorly understood. In previous work, we developed a method to identify direct mRNA targets of microRNA using patient matched microRNA/mRNA expression data using an anti-correlation signature. This method, applied to clear cell Renal Cell Carcinoma (ccRCC), revealed many new regulatory pathways compromised in ccRCC. In the present paper, we apply this method to identify dysregulated microRNA/mRNA mechanisms in ovarian cancer using data from The Cancer Genome Atlas (TCGA).
  
  
  METHODS
  TCGA Microarray data was normalized and samples whose class labels (tumour or normal) were ambiguous with respect to consensus ensemble K-Means clustering were removed. Significantly anti-correlated and correlated genes/microRNA differentially expressed between tumour and normal samples were identified. TargetScan was used to identify gene targets of microRNA.
  
  
  RESULTS
  We identified novel microRNA/mRNA mechanisms in ovarian cancer. For example, the expression level of RAD51AP1 was found to be strongly anti-correlated with the expression of hsa-miR-140-3p, which was significantly down-regulated in the tumour samples. The anti-correlation signature was present separately in the tumour and normal samples, suggesting a direct causal dysregulation of RAD51AP1 by hsa-miR-140-3p in the ovary. Other pairs of potentially biological relevance include: hsa-miR-145/E2F3, hsa-miR-139-5p/TOP2A, and hsa-miR-133a/GCLC. We also identified sets of positively correlated microRNA/mRNA pairs that are most likely result from indirect regulatory mechanisms.
  
  
  CONCLUSIONS
  Our findings identify novel microRNA/mRNA relationships that can be verified experimentally. We identify both generic microRNA/mRNA regulation mechanisms in the ovary as well as specific microRNA/mRNA controls which are turned on or off in ovarian tumours. Our results suggest that the disease process uses specific mechanisms which may be significant for their utility as early detection biomarkers or in the development of microRNA therapies in treating ovarian cancers. The positively correlated microRNA/mRNA pairs suggest the existence of novel regulatory mechanisms that proceed via intermediate states (indirect regulation) in ovarian tumorigenesis.
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, NJ, USA. milesgr@umdnj.edu
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Miles
authors.forename: Michael
authors.initials: M
authors.lastname: Seiler
authors.forename: Lorna
authors.initials: L
authors.lastname: Rodriguez
authors.forename: Gunaretnam
authors.initials: G
authors.lastname: Rajagopal
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics; D016000:Cluster Analysis; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D050699:E2F3 Transcription Factor / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010051:Ovarian Neoplasms; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C548234:MIRN133 microRNA, human; C555098:MIRN139 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; C544302:Mirn140 microRNA, human; D000075223:Poly-ADP-Ribose Binding Proteins; C110410:RAD51AP1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; D005721:Glutamate-Cysteine Ligase