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.
Highlights
Small-cell lung cancer (SCLC) constitutes approximately 15% of all lung cancers and is one of the most common malignant tumors worldwide [1, 2]
Overexpression of miR-24-3p into H446/EP cells led to reduction of the autophagyassociated gene 4A (ATG4A) protein level, allowing small-cell lung cancer (SCLC) cells to resensitize to VP16–DDP
We focused on determining the role of miRNAs in the development of VP16–DDP resistance in SCLC related to autophagy
Summary
Small-cell lung cancer (SCLC) constitutes approximately 15% of all lung cancers and is one of the most common malignant tumors worldwide [1, 2]. SCLC is characterized by an aggressive propensity for early dissemination and rapid development of chemoresistance during the treatment, patients initially show high response rates [4]. Patients with resistant disease suffer early relapse; overall survival at 5 years is less than 5% [4]. MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post-transcriptional level. They bind to 3′-untranslated regions (3′-UTR) of target mRNAs, leading to mRNA destabilization and translational repression [5]. Specific miRNAs are differentially expressed between normal and cancer cells [8], and modulate cancer therapy response and resistance [9]. MiRNA expression in chemoresistant SCLC is not widely investigated, and the mechanisms that underlie aberrant miRNAs expression are not well understood
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