Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma

• Published in: Experimental and molecular pathology Vol. 95; no. 1; pp. 62 - 67
• Main Authors: Hudson, Jena, Duncavage, Eric, Tamburrino, Anna, Salerno, Paolo, Xi, Liqiang, Raffeld, Mark, Moley, Jeffrey, Chernock, Rebecca D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2013
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Aged; Carcinoma, Neuroendocrine; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Medullary thyroid carcinoma; microRNA; MicroRNAs - genetics; Middle Aged; miR-10a; miR-375; miR-455; Monocarboxylic Acid Transporters - genetics; Mutation; Phosphoproteins - genetics; Phosphoproteins - metabolism; Proto-Oncogene Proteins c-ret - genetics; Real-Time Polymerase Chain Reaction; Reference Values; Symporters; Thyroid Neoplasms - genetics; Transcription Factors; YAP1; YAP1; miR-455; microRNA; miR-375; Medullary thyroid carcinoma; miR-10a
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2013.05.001

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. •We examined the expression of over 700 miRNAs in medullary thyroid carcinoma (MTC).•miR-375 and miR-10a were overexpressed and miR-455 was underexpressed in MTC.•A known target of miR-375 and a growth inhibitor, YAP1, was downregulated in MTC.•Inhibition of YAP1 by miR-375 may be important for MTC development or progression.