Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States.
Exp Mol Pathol. 2013 Aug;95(1):62-7. doi: 10.1016/j.yexmp.2013.05.001. Epub 2013 May 16.
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.
微小 RNA 是一种原始的基因表达调控机制，似乎对细胞发育至关重要，并且可能在肿瘤发生发展中发挥重要作用。关于甲状腺髓样癌的遗传学已经有了很多了解，因为大约 25%的甲状腺髓样癌是遗传性的，并且在 RET 基因中有生殖系激活突变。大约 50%的散发性甲状腺髓样癌也存在体细胞 RET 突变。然而，很少有研究评估微小 RNA 表达在这些肿瘤中的作用。从 15 例甲状腺髓样癌[10 例有 RET 突变（3 例遗传性）和 5 例无 RET 突变]和 5 例非肿瘤甲状腺组织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 测定法通过实时 PCR 定量 754 个靶标的微小 RNA 表达。三种微小 RNA 表现出显著的差异表达，并通过实时 PCR 在一个更大的 59 例病例队列中进行验证。还通过实时 PCR 研究了潜在下游靶标和上游调节剂的表达。miR-375 和 miR-10a 表达明显上调，而 miR-455 表达下调。所有 3 种微小 RNA 的表达在更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)）。在 RET 突变阳性和阴性肿瘤之间以及散发和遗传性肿瘤之间未发现微小 RNA 表达的显著差异。miR-375 的潜在下游靶标 YAP1（生长抑制剂）和 SLC16a2（甲状腺激素转运蛋白）的表达下调，提示 miR-375 是这些基因表达的负调节剂。因此，miR-375、miR-10a 和 miR-455 的差异表达可能对肿瘤的发生发展很重要，或者反映甲状腺髓样癌的 C 细胞系。此外，生长抑制剂 YAP1 被确定为 miR-375 的潜在重要下游靶标。
