title: Mir-24-3p downregulation contributes to VP16-DDP resistance in small-cell lung cancer by targeting ATG4A.
abstract: Although the combination of etoposide (VP16) and cisplatin (DDP) is widely used as a first-line treatment for advanced-stage small-cell lung cancer (SCLC), chemoresistance limits its clinical use. Abnormalities of autophagy are associated with tumor chemoresistance. The present study found that miR-24-3p, a recently discovered microRNA, is significantly downregulated in VP16-DDP-resistant SCLC cells (H446/EP) compared with VP16-DDP-sensitive parent cells (H446). Forced expression of miR-24-3p sensitized H446/EP cells to VP16-DDP treatment because of a blockade of autophagic activity. We further found that downregulated miR-24-3p enhanced autophagy activation as it directly targets and inhibits autophagy-associated gene 4A (ATG4A). Overexpression of miR-24-3p into H446/EP cells led to reduction of the ATG4A protein level, allowing SCLC cells to resensitize to VP16-DDP. We conclude that miR-24-3p regulates autophagy by targeting ATG4A. Inhibition of autophagy by increasing miR-24-3p could be the basis of a strategy to prevent and treat SCLC with combination chemotherapy, particularly in chemoresistant disease.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Banzhou
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Yitian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Haizhu
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071183:Autophagy-Related Proteins; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000096:biosynthesis*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000235:genetics*; D014162:Transfection
chemical_list: D000071183:Autophagy-Related Proteins; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D005047:Etoposide; C474025:ATG4A protein, human; D003546:Cysteine Endopeptidases; D002945:Cisplatin