title: A microRNA activity map of human mesenchymal tumors: connections to oncogenic pathways; an integrative transcriptomic study.
abstract: BACKGROUND
  MicroRNAs (miRNAs) are nucleic acid regulators of many human mRNAs, and are associated with many tumorigenic processes. miRNA expression levels have been used in profiling studies, but some evidence suggests that expression levels do not fully capture miRNA regulatory activity. In this study we integrate multiple gene expression datasets to determine miRNA activity patterns associated with cancer phenotypes and oncogenic pathways in mesenchymal tumors - a very heterogeneous class of malignancies.
  
  
  RESULTS
  Using a computational method, we identified differentially activated miRNAs between 77 normal tissue specimens and 135 sarcomas and we validated many of these findings with microarray interrogation of an independent, paraffin-based cohort of 18 tumors. We also showed that miRNA activity is imperfectly correlated with miRNA expression levels. Using next-generation miRNA sequencing we identified potential base sequence alterations which may explain differential activity. We then analyzed miRNA activity changes related to the RAS-pathway and found 21 miRNAs that switch from silenced to activated status in parallel with RAS activation. Importantly, nearly half of these 21 miRNAs were predicted to regulate integral parts of the miRNA processing machinery, and our gene expression analysis revealed significant reductions of these transcripts in RAS-active tumors. These results suggest an association between RAS signaling and miRNA processing in which miRNAs may attenuate their own biogenesis.
  
  
  CONCLUSIONS
  Our study represents the first gene expression-based investigation of miRNA regulatory activity in human sarcomas, and our findings indicate that miRNA activity patterns derived from integrated transcriptomic data are reproducible and biologically informative in cancer. We identified an association between RAS signaling and miRNA processing, and demonstrated sequence alterations as plausible causes for differential miRNA activity. Finally, our study highlights the value of systems level integrative miRNA/mRNA assessment with high-throughput genomic data, and the applicability of paraffin-tissue-derived RNA for validation of novel findings.
authors: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Elena
authors: E
authors: Fountzilas
authors: Andrew D
authors: AD
authors: Kelly
authors: Antonio R
authors: AR
authors: Perez-Atayde
authors: Jeffrey
authors: J
authors: Goldsmith
authors: Panagiotis A
authors: PA
authors: Konstantinopoulos
authors: Nancy
authors: N
authors: Francoeur
authors: Mick
authors: M
authors: Correll
authors: Renee
authors: R
authors: Rubio
authors: Lan
authors: L
authors: Hu
authors: Mark C
authors: MC
authors: Gebhardt
authors: John
authors: J
authors: Quackenbush
authors: Dimitrios
authors: D
authors: Spentzos
mesh_terms: D000465:Algorithms; D015331:Cohort Studies; D019295:Computational Biology; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D018204:Neoplasms, Connective and Soft Tissue / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D018631:ras Proteins