Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma.
Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma.
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DOI：
10.1016/j.yexmp.2013.05.001
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发表时间：
2013-08
影响因子：
3.6
通讯作者：
Chernock, Rebecca D.
中科院分区：
文献类型：
--
作者：
Hudson, Jena;Duncavage, Eric;Tamburrino, Anna;Salerno, Paolo;Xi, Liqiang;Raffeld, Mark;Moley, Jeffrey;Chernock, Rebecca D.
microRNA是基因表达控制的原始机制，似乎对细胞发育至关重要，并可能在肿瘤发生中发挥重要作用。关于甲状腺髓样癌的遗传学已知很多，因为大约25%是遗传性的，并且在RET基因中具有生殖系激活突变。大约50%的散发性甲状腺髓样癌中也可见体细胞RET突变。然而，很少有研究评估microRNA表达在这些肿瘤中的作用。从15例甲状腺髓样癌[10例RET突变（3例遗传性）和5例无RET突变]和5例非肿瘤甲状腺的福尔马林固定石蜡包埋组织块中提取DNA和RNA。使用ABI OpenArray miRNA测定通过真实的时间PCR定量754个靶标的miRNA表达。三种miRNAs显示出显著的差异表达，并通过实时PCR在59例病例的较大队列中进行了验证。还通过实时PCR研究了潜在的下游靶标和上游调节剂的表达。miR-375和miR-10a在甲状腺髓样癌中显著过表达，而miR-455则表达不足。所有3种miRNA的表达在较大的病例队列中得到验证（miR-375，p = 3.3×10−26; miR-10a，p = 5.6×10−14; miR-455，p = 2.4×10−4）。RET突变阳性和阴性肿瘤之间以及散发性和遗传性肿瘤之间的miRNA表达无显著差异。miR-375的潜在下游靶点YAP 1（生长抑制剂）和SLC 16 a2（甲状腺激素转运蛋白）的表达在肿瘤中下调，表明miR-375是这些基因表达的负调控因子。因此，miR-375、miR-10a和miR-455的差异表达可能对甲状腺髓样癌的肿瘤发展和/或反映c细胞谱系是重要的。此外，生长抑制剂YAP 1被鉴定为miR-375的潜在重要下游靶点。
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.
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