title: MicroRNA profiling of sporadic and hereditary medullary thyroid cancer identifies predictors of nodal metastasis, prognosis, and potential therapeutic targets.
abstract: OBJECTIVE
  While the molecular basis of hereditary medullary thyroid cancer (HMTC) has been well defined, little is known about the molecular pathogenesis of sporadic medullary thyroid cancer (SMTC). In addition, microRNAs (miRNAs) have been shown to be important diagnostic and prognostic markers in cancer but have not been defined in MTC. Our aim was to study the miRNA profile of MTC to identify prognostic biomarkers and potential therapeutic targets.
  
  
  METHODS
  MiRNA microarray profiling was carried out in fresh frozen tissues from patients with SMTC (n = 12) and HMTC (n = 7). Differential expression of three miRNAs was confirmed in a validation cohort of SMTC and HMTC samples (n = 45) using quantitative reverse transcriptase-PCR and correlated with clinical outcomes. The functional role of a selected miRNA was investigated in vitro in the human medullary thyroid carcinoma cell line (TT cells) using cell proliferation assays and Western blotting analysis.
  
  
  RESULTS
  MiRs-183 and 375 were overexpressed (P = 0.001; 0.031) and miR-9* was under-expressed (P = 0.011) in SMTC versus HMTC. Overexpression of miRs-183 and 375 in MTC predicted lateral lymph node metastases (P < 0.001; P = 0.001) and was associated with residual disease (P = 0.001; 0.003), distant metastases (P = 0.003; 0.001), and mortality (P = 0.01; 0.011). Knock down of miR-183 expression in the TT cell line induced a significant decrease in the viable cell count and upregulation of the protein LC3B, which is associated with autophagy.
  
  
  CONCLUSIONS
  Our data indicate that miRNAs play a pivotal role in the biology of MTC and represent an important class of prognostic biomarkers and therapeutic targets warranting further investigation.
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia.
authors.forename: Deepak
authors.initials: D
authors.lastname: Abraham
authors.forename: Nicole
authors.initials: N
authors.lastname: Jackson
authors.forename: Justin S
authors.initials: JS
authors.lastname: Gundara
authors.forename: JingTing
authors.initials: J
authors.lastname: Zhao
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.forename: Leigh
authors.initials: L
authors.lastname: Delbridge
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
authors.forename: Stan B
authors.initials: SB
authors.lastname: Sidhu
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018278:Carcinoma, Neuroendocrine; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D015203:Reproducibility of Results; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000628:therapy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C533449:MIRN183 microRNA, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs