title: MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma.
abstract: BACKGROUND
  Papillary thyroid carcinoma (PTC) has relatively indolent behavior, although some tumors recur and disseminate to distant sites. The aggressive biological behavior of PTC is difficult to predict. MicroRNAs (miRNAs) are dysregulated in various tumors types, and some of them serve as markers of poor prognosis. In this study, we evaluated miRNA expression as a marker of more aggressive behavior in PTC.
  
  
  METHODS
  miRNA array was used to identify a subset of differentially expressed miRNAs between aggressive and nonaggressive PTC. These miRNAs were further validated by real-time RT-PCR in a cohort of 17 PTC with local tumor recurrence or distant metastases and 15 PTC with no extrathyroidal dissemination and correlated with BRAF, RAS, and RET/PTC mutations and MET expression.
  
  
  RESULTS
  The miRNA array identified miR-146b, miR-221, miR-222, miR-155, miR-31 upregulation and miR-1, miR-34b, miR-130b, miR-138 downregulation in aggressive compared with nonaggressive PTC. Significant miRNA deregulation was confirmed in the validation cohort, with upregulation of miR-146b and miR-222 and downregulation of miR-34b and miR-130b seen in aggressive PTC. Among BRAF-positive tumors, miR-146b showed strong association with aggressive PTC. MET was identified as a potential target gene for 2 downregulated miRNAs (miR-34b and miR-1), and significantly higher level of MET expression was observed in aggressive PTC.
  
  
  CONCLUSIONS
  We demonstrate that miR-146b, miR-222, miR-34b, miR-130b are differentially expressed in aggressive compared with nonaggressive PTC. Among BRAF-positive tumors, overexpression of miR-146b was associated with aggressive behavior, suggesting that it may further refine the prognostic importance of BRAF.
authors.affiliation: Department of Surgery, Section of Endocrine Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Linwah
authors.initials: L
authors.lastname: Yip
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kelly
authors.forename: Yongli
authors.initials: Y
authors.lastname: Shuai
authors.forename: Michaele J
authors.initials: MJ
authors.lastname: Armstrong
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
authors.forename: Sally E
authors.initials: SE
authors.lastname: Carty
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000556:secondary; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000556:secondary; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012334:RNA, Neoplasm; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf