title: Regulation of autophagy by miR-30d impacts sensitivity of anaplastic thyroid carcinoma to cisplatin.
abstract: 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.
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China. Electronic address: zhangyi@suda.edu.cn.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: W Q
authors.initials: WQ
authors.lastname: Yang
authors.affiliation: Department of Surgery, School of Medicine, Ohio State University, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Ren
authors.affiliation: Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: X C
authors.initials: XC
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: X P
authors.initials: XP
authors.lastname: Liu
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Ming
authors.affiliation: Department of Surgery, School of Medicine, Ohio State University, USA.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: J R
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Y B
authors.initials: YB
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Hematology Center of Cyrus Tang Medical Institute, Affiliated Changshu Hospital, Soochow University, Suzhou, Jiangsu Province, China; Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: jyang2@hmc.psu.edu.
authors.forename: J M
authors.initials: JM
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C546086:MIRN30b microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D002945:Cisplatin
keywords: Anaplastic thyroid cancer; Apoptosis; Autophagy; Beclin1; Cisplatin; miR-30d