Attenuation of deregulated miR-369-3p expression sensitizes non-small cell lung cancer cells to cisplatin via modulation of the nucleotide sugar transporter SLC35F5.

Deregulation of the microRNAs (miRNAs), a cluster of important posttranscriptional regulators, has been frequently associated with lung cancer (LCa). However, the emerging mechanism for how miRNAs is linked causally in the development of LCa chemoresistance is poorly understood. Herein, we established for the time the up-regulation of miR-369-3p in cisplatin (DDP)-resistant nonsmall cell lung cancer (NSCLC) tissues and cells. Its deregulation was found to be correlated to the magnitude of malignancy in well-characterized LCa cells. Functionally, inhibition of miR-369-3p sensitized LCa cells to DDP and suppressed the invasive capability in the presence of DDP treatment, whereas miR-369-3p overexpression promoted DDP resistance and thereby enhanced LCa cells invasiveness. Mechanistically, bioinformatics coupled with luciferase and gain-of-function, loss-of-function assays revealed that miR-369-3p may regulate DDP chemoresistance by directly targeting the 3' untranslated region (UTR) of human solute carrier 35F5 (SLC35F5), as application of miR-369-3p inhibitors or reintroduction of epigenetically silenced SLC35F5 both individually sensitized LCa cells to DDP, but combined treatment with miR-369-3p inhibitors and SLC35F5 overexpression failed to sensitized LCa cells further to DDP-elicited cell death. Our results provide evidence that the oncomiR effect of miR-369-3p may be mediated through disrupting the nucleotide sugar transportation and that SLC35F5 is a key effector of this chemoresistance-promoting activity.

Suppression of EIF4G2 by miR-379 potentiates the cisplatin chemosensitivity in nonsmall cell lung cancer cells.

Although microRNAs and EIF4G2 are both known to play pivotal roles in cancer progression, it remains unknown whether these pathways regulate chemosensitivity in a coordinated manner. Here, we show that miR-379 expression is significantly downregulated in chemoresistant nonsmall cell lung cancer (NSCLC) tissues and cells. Manipulation of miR-379 levels could alter the in vitro and in vivo cisplatin (CDDP) resistance in lung cancer (LCa) cells. Mechanistically, miR-379 potentiated LCa chemosensitivity via modulation of CDDP-induced apoptosis by directly targeting the EIF4G2 3'UTR. Additionally, we observed an inverse correlation between miR-379 and EIF4G2 expression in LCa tissues from patients with CDDP-based chemotherapy. Together, our findings shed new light on the potential involvement of miR-379/EIF4G2 cascade in the pathogenesis of CDDP resistance in LCa.