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 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.

MicroRNA-15b/16 Attenuates Vascular Neointima Formation by Promoting the Contractile Phenotype of Vascular Smooth Muscle Through Targeting YAP

“…During preparation of the manuscript, we noticed that miR-15a/16 targeted YAP to inhibit cell proliferation and migration in gastric adenocarcinoma cells 35 . In addition to miR-16 family members, YAP can be regulated by miR-375 in liver 36 , lung 37 , pancreatic 38 and thyroid cancer cells 39 . Additionally, miR-141, 200a and 506 have been implicated in regulating YAP expression in esophageal squamous cell carcinoma 40 , breast 41 and hepatoma cancer cells 42 , respectively.…”

The PDCD4/miR-21 pathway in medullary thyroid carcinoma

“…The role of microRNA in the pathogenesis and prognosis of MTC has recently been investigated [18][19][20][21]. Only one study investigated the PDCD4/miR-21 pathway in a small series of MTCs, finding it significantly dysregulated [22].…”

Circulating tumor cells and miRNAs as prognostic markers in neuroendocrine neoplasms

“…On the contrary, miRNA expression profiles in medullary thyroid carcinoma (MTC) have been evaluated in few studies (Nikiforova et al 2008, Abraham et al 2011, Mian et al 2012, Hudson et al 2013, Santarpia et al 2013, Gundara et al 2014, Pennelli et al 2015, Lassalle et al 2016, out of which only three evaluated the prognostic role of miRNAs in MTC. Abraham and coworkers 24:6 (Abraham et al 2011) evaluated the expression of four miRNAs (miR-183, miR 375, miR 9 and miR 9*) selected on the basis of their reported significance in other cancers.…”