Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
Biochem Pharmacol. 2014 Feb 15;87(4):562-70. doi: 10.1016/j.bcp.2013.12.004. Epub 2013 Dec 15.
miR-30d has been observed to be significantly down-regulated in human anaplastic thyroid carcinoma (ATC), and is believed to be an important event in thyroid cell transformation. In this study, we found that miR-30d has a critical role in modulating sensitivity of ATC cells to cisplatin, a commonly used chemotherapeutic drug for treatment of this neoplasm. Using a mimic of miR-30d, we demonstrated that miR-30d could negatively regulate the expression of beclin 1, a key autophagy gene, leading to suppression of the cisplatin-activated autophagic response that protects ATC cells from apoptosis. A reporter gene assay demonstrated that the binding sequences of miR-30d in the beclin 1-3' UTR was the region required for the inhibition of beclin 1 expression by this miRNA. We further showed that inhibition of the beclin 1-mediated autophagy by the miR-30d mimic sensitized ATC cells to cisplatin both in vitro (cell culture) and in vivo (animal xenograft model). These results suggest that dysregulation of miR-30d in ATC cells is responsible for the insensitivity to cisplatin by promoting autophagic survival. Thus, miR-30d may be exploited as a potential target for therapeutic intervention in the treatment of ATC.
miR-30d 在人类间变性甲状腺癌（ATC）中观察到明显下调，被认为是甲状腺细胞转化中的一个重要事件。在这项研究中，我们发现 miR-30d 在调节 ATC 细胞对顺铂（一种常用于治疗这种肿瘤的化疗药物）敏感性方面具有关键作用。使用 miR-30d 的模拟物，我们证明 miR-30d 可以负调控自噬基因 beclin 1 的表达，从而抑制顺铂激活的自噬反应，保护 ATC 细胞免受凋亡。报告基因测定表明，miR-30d 在 beclin 1-3'UTR 中的结合序列是该 miRNA 抑制 beclin 1 表达所必需的区域。我们进一步表明，miR-30d 模拟物抑制 beclin 1 介导的自噬可使 ATC 细胞对顺铂在体外（细胞培养）和体内（动物异种移植模型）均敏感。这些结果表明，ATC 细胞中 miR-30d 的失调通过促进自噬存活导致对顺铂的不敏感。因此，miR-30d 可能被用作治疗 ATC 的潜在治疗靶点。
