Tumor Suppressive MicroRNA-124a Inhibits Stemness and Enhances Gefitinib Sensitivity of Non-small Cell Lung Cancer Cells by Targeting Ubiquitin-specific Protease 14

Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, ubiquitin-specific protease 14 (USP14) was confirmed to be a direct target of hsa-miR-124a. Furthermore, concomitant low hsa-miR-124a expression and high USP14 expression were correlated with a shorter median OS and PFS in NSCLC patients. Cellular functional analysis verified that the tumor suppressor hsa-miR-124a negatively regulated cell growth and self-renewal, and promoted apoptosis and gefitinib sensitivity of lung cancer stem cells by suppressing its target gene USP14. Our results provide the first evidence that USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14. Thus, hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC.