Regulation of autophagy by miR-30d impacts sensitivity of anaplastic thyroid carcinoma to cisplatin

• Published in: Biochemical pharmacology Vol. 87; no. 4; pp. 562 - 570
• Main Authors: Zhang, Y., Yang, W.Q., Zhu, H., Qian, Y.Y., Zhou, L., Ren, Y.J., Ren, X.C., Zhang, L., Liu, X.P., Liu, C.G., Ming, Z.J., Li, B., Chen, B., Wang, J.R., Liu, Y.B., Yang, J.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.02.2014
• Subjects: 3' Untranslated Regions - drug effects; 3' Untranslated Regions - physiology; Anaplastic thyroid cancer; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - biosynthesis; Apoptosis Regulatory Proteins - genetics; Autophagy; Autophagy - drug effects; Autophagy - genetics; Beclin-1; Beclin1; Cell Line, Tumor; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Humans; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred BALB C; MicroRNAs - genetics; miR-30d; Protein Binding - drug effects; Protein Binding - physiology; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - genetics; Xenograft Model Antitumor Assays - methods; Anaplastic thyroid cancer; Beclin1; miR-30d; Autophagy; Cisplatin; Apoptosis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2013.12.004

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.