title: MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib.
abstract: Chemotherapy-induced autophagy activation often contributes to cancer resistance. MiRNA-30a (miR-30a) is a potent inhibitor of autophagy by downregulating Beclin-1. In this study, we characterized the role of miR-30a in sorafenib-induced activity in renal cell carcinoma (RCC) cells. We found that expression of miR-30a was significantly downregulated in several human RCC tissues and in RCC cell lines. Accordingly, its targeted gene Beclin-1 was upregulated. Sorafenib activated autophagy in RCC cells (786-0 and A489 lines), evidenced by p62 degradation, Beclin-1/autophagy protein 5 (ATG-5) upregulation and light chain (LC)3B-I/-II conversion. Exogenously expressing miR-30a in 786-0 or A489 cells inhibited Beclin-1 expression and enhanced sorafenib-induced cytotoxicity. In contrast, knockdown of miR-30a by introducing antagomiR-30a increased Beclin-1 expression, and inhibited sorafenib-induced cytotoxicity against RCC cells. Autophagy inhibitors, including chloroquine, 3-methyaldenine or Bafliomycin A1, enhanced sorafenib activity, causing substantial cell apoptosis. Meanwhile, knockdown of Beclin-1 or ATG-5 by targeted siRNAs also increased sorafenib-induced cytotoxicity in above RCC cells. These findings indicate that dysregulation of miR-30a in RCC may interfere with the effectiveness of sorafenib-mediated apoptosis by an autophagy-dependent pathway, thus representing a novel potential therapeutic target for RCC.
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China; The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Donghua
authors.initials: D
authors.lastname: Gu
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Pan
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qian
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Boxin
authors.initials: B
authors.lastname: Xue
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Dongrong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Radiotherapy of the Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China. Electronic address: zhoujundong330@163.com.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: bingzhengnantong@163.com.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Shan
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000077157:Sorafenib; D015854:Up-Regulation
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; C546086:MIRN30b microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D010671:Phenylurea Compounds; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D009536:Niacinamide; D000077157:Sorafenib
keywords: Autophagy; Beclin-1; Chemo-sensitization; Renal cell carcinoma; Sorafenib; miRNA-30a