Mir-24-3p downregulation contributes to VP16-DDP resistance in small-cell lung cancer by targeting <i>ATG4A</i>

Abstract

// Banzhou Pan 1* , Yitian Chen 1* , Haizhu Song 1 , Yichen Xu 1 , Rui Wang 1 and Longbang Chen 1 1 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China * Co-first authors Correspondence: Longbang Chen, email: // Keywords : miR-24-3p, autophagy, chemoresistance, small-cell lung cancer, mechanism, ATG4A Received : September 15, 2014 Accepted : November 15, 2014 Published : November 16, 2014 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&ndash;DDP-resistant SCLC cells (H446/EP) compared with VP16&ndash;DDP-sensitive parent cells (H446). Forced expression of miR-24-3p sensitized H446/EP cells to VP16&ndash;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&ndash;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.