Over expression of miR-10 a and miR-375 and down regulation of YAP 1 in medullary thyroid carcinoma

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 were 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 were 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 downregulated 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 the reflect c-cell lineage of medullary thyroid carcinoma. Furthermore, the growth inhibitor YAP1 is identified as a potential important downstream target of miR-375. © 2013 Elsevier Inc. All rights reserved. Address for correspondence and reprints: Rebecca D. Chernock, MD, Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO, 63110; Fax: 314-362-8950; Telephone: 314-454-8854; rchernock@path.wustl. edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure/Conflict of Interest: The authors have no conflict of interest to declare. NIH Public Access Author Manuscript Exp Mol Pathol. Author manuscript; available in PMC 2014 August 01. Published in final edited form as: Exp Mol Pathol. 2013 August ; 95(1): 62–67. doi:10.1016/j.yexmp. 2013.05. 001. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript