TY - JOUR
T1 - Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma
AU - Hudson, Jena
AU - Duncavage, Eric
AU - Tamburrino, Anna
AU - Salerno, Paolo
AU - Xi, Liqiang
AU - Raffeld, Mark
AU - Moley, Jeffrey
AU - Chernock, Rebecca D.
N1 - Funding Information:
We thank Xiaopei Zhu M.D. for technical assistance with the PCR experiments and James S Lewis Jr. for critical review of the manuscript. We also thank Chris Sawyer and the Washington University Genome Technology Access Core (GTAC) for their assistance in running the PCR arrays. The GTAC is partially supported by NCI Cancer Center support grant # P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant # UL1RR024992 from the National Center for Research Resources (NCRR) , a component of the National Institutes of Health (NIH) , and NIH Roadmap for Medical Research .
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - Medullary thyroid carcinoma
KW - MiR-10a
KW - MiR-375
KW - MiR-455
KW - MicroRNA
KW - YAP1
UR - http://www.scopus.com/inward/record.url?scp=84879176399&partnerID=8YFLogxK
U2 - 10.1016/j.yexmp.2013.05.001
DO - 10.1016/j.yexmp.2013.05.001
M3 - Article
C2 - 23685355
AN - SCOPUS:84879176399
SN - 0014-4800
VL - 95
SP - 62
EP - 67
JO - Experimental and Molecular Pathology
JF - Experimental and Molecular Pathology
IS - 1
ER -