microRNAs (miRNAs) have been implicated to play critical roles in non-small celllung cancer (NSCLC) progression and participate in the regulation of drug resistance during cancer chemotherapy. However, the underlying molecular mechanism of how miR-539 modulates the chemosensitivity to cisplatin (DDP) in NSCLC cells remains largely unknown. In this study, we found that miR-539 was significantly downregulated in DDP-resistant cell lines (A549/DDP and H1299/DDP). Overexpression of miR-539 enhanced the sensitivity of DDP-resistant NSCLC cells to DDP by suppressing cell proliferation, causing cell cycle arrest, inducing apoptosis, repressing invasion and migration. Whereas, downregulation of miR-539 inhibited the sensitivity of parental NSCLC cells to DDP by promoting cell proliferation and decreasing DDP-induced apoptosis. Furthermore, the luciferase report assay identified doublecortin-like kinase 1 (DCLK1) was a direct target of miR-539. Knockdown of DCLK1 mimicked the function of miR-539-mediated cell chemosensitivity in DDP-resistant NSCLC cells, while restoration of DCLK1 reversed the effect of miR-539 overexpression. We also found that P13 K/AKT/mTOR signaling pathway was also involved in miR-539/DCLK1 axis -mediated chemosensitivity in DDP-resistant NSCLC cells. Additionally, the downregulation of miR-539 was closely correlated with severe clinicopathological parameters including the upregulation of DCLK1, chemosensitivity to DDP, and tumor aggressiveness in NSCLC patients. In conclusion, miR-539 increased the chemosensitivity to DDP in NSCLC cells by directly targeting DCLK1, which might provide potential biomarkers for DDP-resistant NSCLC therapy.
Keywords: Chemoresistance; Cisplatin; DCLK1; Non-small celllung cancer; miR-539.
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