title: miR-142-3p down-regulation contributes to thyroid follicular tumorigenesis by targeting ASH1L and MLL1.
abstract: BACKGROUND
  A previous micro-RNA expression profile of thyroid follicular adenomas identified miR-142 precursor among the miRNAs downregulated in the neoplastic tissues compared to normal thyroid gland.
  
  
  OBJECTIVE
  The aim of this work has been to assess the expression of miR-142-3p in a large panel of follicular thyroid adenomas and carcinomas and evaluate its effect on thyroid cell proliferation and target expression.
  
  
  METHODS
  The expression of miR-142-3p was analyzed by qRT-PCR in thyroid follicular adenomas and carcinomas, compared to normal thyroids. MiR-142-3p expression was restored in WRO cells and the effects on cell proliferation and target expression were evaluated.
  
  
  RESULTS
  Here we show that miR-142-3p is downregulated in FTAs, FTCs, and FVPTCs. MiR-142-3p was demonstrated to reduce the proliferation rate of WRO and FTC133 cells, supporting its tumor suppressor role in thyroid cancerogenesis. Moreover, this microRNA was able to downregulate the expression of ASH1L and MLL1, by direct and indirect mechanisms, respectively. Consistently, an inverse correlation between miR-142-3p expression and ASH1L and MLL1 proteins was found in thyroid follicular adenomas and carcinomas. ASH1L and MLL1, which belong to the Trithorax group (TrxG) proteins and are major regulators of Homeobox gene expression, maintain active target gene transcription by histone 3 lysine 4 methylation. Interestingly, we found that FTCs and FTC cell lines express tumor specific, shorter forms of the two proteins. The capability of miR-142-3p to modulate the levels of these tumor-associated forms and to reactivate thyroid-specific Hox gene expression, likely contributes to its tumor suppressive function.
  
  
  CONCLUSIONS
  These data demonstrate that miR-142-3p downregulation has a role in thyroid tumorigenesis, by regulating ASH1L and MLL1.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (M.C., F.P., E.R., A.U.B., A.F., S.B., A.F.), Università degli Studi di Napoli "Federico II," 80131 Naples, Italy; Department of Pathology (M. D-P.), Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Université Lyon 1, 69495 Pierre Bénite, France; CEINGE (M.G., L.D.V.), Biotecnologie Avanzate, 80145 Naples, Italy; Istituto dei Tumori di Napoli "G. Pascale" (C.A., G.C.) Via Mariano Semmola, 52, 80131 Naples, Italy; Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell'Area Critica (L.T.), University of Pisa, I-56126 Pisa, Italy; and Instituto Nacional de Câncer (A.F.), 20230-130 Rio de Janeiro, RJ, Brazil.
authors.forename: Marianna
authors.initials: M
authors.lastname: Colamaio
authors.forename: Francesca
authors.initials: F
authors.lastname: Puca
authors.forename: Elvira
authors.initials: E
authors.lastname: Ragozzino
authors.forename: Marica
authors.initials: M
authors.lastname: Gemei
authors.forename: Myriam
authors.initials: M
authors.lastname: Decaussin-Petrucci
authors.forename: Concetta
authors.initials: C
authors.lastname: Aiello
authors.forename: André Uchimura
authors.initials: AU
authors.lastname: Bastos
authors.forename: Antonella
authors.initials: A
authors.lastname: Federico
authors.forename: Gennaro
authors.initials: G
authors.lastname: Chiappetta
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.forename: Liborio
authors.initials: L
authors.lastname: Torregrossa
authors.forename: Sabrina
authors.initials: S
authors.lastname: Battista
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C555159:MIRN142 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C490911:ASH1L protein, human; D011495:Histone-Lysine N-Methyltransferase