title: Prognostic implications of miR-146b expression and its functional role in papillary thyroid carcinoma.
abstract: BACKGROUND
  Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model.
  
  
  METHODS
  Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined.
  
  
  RESULTS
  Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis.
  
  
  CONCLUSIONS
  Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC.
authors.affiliation: Division of Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, 123 Ta-Pei Road, Niao-sung District, Kaohsiung City, Taiwan.
authors.forename: Chen-Kai
authors.initials: CK
authors.lastname: Chou
authors.forename: Kuender D
authors.initials: KD
authors.lastname: Yang
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Chou
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Huang
authors.forename: Yueh-Wen
authors.initials: YW
authors.lastname: Lan
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Lee
authors.forename: Hong-Yo
authors.initials: HY
authors.lastname: Kang
authors.forename: Rue-Tsuan
authors.initials: RT
authors.lastname: Liu
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf