title: Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma.
abstract: MicroRNAs are a primordial mechanism of gene expression control that appear to be crucial to cellular development and may play an important role in tumor development. Much is known about the genetics of medullary thyroid carcinomas, as approximately 25% are hereditary and harbor germ line activating mutations in the RET gene. Somatic RET mutations are also seen in roughly 50% of sporadic medullary thyroid carcinomas. Few studies, however, have evaluated the role of microRNA expression in these tumors. DNA and RNA were extracted from formalin-fixed paraffin-embedded tissue blocks of 15 medullary thyroid carcinomas [10 with RET mutations (3 hereditary) and 5 without RET mutations] and 5 non-tumor thyroid glands. miRNA expression of 754 targets was quantitated by real-time PCR using the ABI OpenArray miRNA assay. Three miRNAs showed significant differential expression and were validated in a larger cohort of 59 cases by real-time PCR. Expression of potential downstream targets and upstream regulators was also investigated by real-time PCR. miR-375 and miR-10a were significantly overexpressed, while miR-455 was underexpressed in medullary thyroid carcinomas. Expression of all 3 miRNAs was validated in the larger cohort of cases (miR-375, p=3.3×10(-26); miR-10a, p=5.6×10(-14); miR-455, p=2.4×10(-4)). No significant differences in miRNA expression were found between RET mutation positive and negative tumors nor between sporadic and hereditary tumors. Expression of the potential downstream targets of miR-375, YAP1 (a growth inhibitor) and SLC16a2 (a transporter of thyroid hormone), was down-regulated in the tumors suggesting that miR-375 is a negative regulator of the expression of these genes. Thus, differential expression of miR-375, miR-10a and miR-455 may be important for tumor development and/or reflect C-cell lineage of medullary thyroid carcinoma. Furthermore, the growth inhibitor YAP1 is identified as a potential important downstream target of miR-375.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: Jena
authors.initials: J
authors.lastname: Hudson
authors.forename: Eric
authors.initials: E
authors.lastname: Duncavage
authors.forename: Anna
authors.initials: A
authors.lastname: Tamburrino
authors.forename: Paolo
authors.initials: P
authors.lastname: Salerno
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Moley
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Chernock
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D018278:Carcinoma, Neuroendocrine; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000235:genetics; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D027981:Symporters; D013964:Thyroid Neoplasms / Q000235:genetics*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C547183:MIRN10 microRNA, human; C540933:MIRN375 microRNA, human; C583404:MIRN455 microRNA, human; D035683:MicroRNAs; D027501:Monocarboxylic Acid Transporters; D010750:Phosphoproteins; C090735:SLC16A2 protein, human; D027981:Symporters; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: Medullary thyroid carcinoma; YAP1; miR-10a; miR-375; miR-455; microRNA