microRNA-203a-3p sensitizes cisplatin through disruption of RAN-dependent RRM2 nuclear localization and mitochondrial stress readouts.

The efficacy of chemotherapeutic drugs is often limited by cancer cells' adaptive pro-survival mechanisms that attenuate treatment response. Here, we observed marked downregulation of miR-203a-3p in OSCC cells upon exposure to cisplatin, which, upon restoration, enhanced cisplatin sensitivity by increasing DNA double-stranded breaks, promoting apoptotic cell death through decreased Bcl-2 and caspase-9/3 activation, elevating reactive oxygen species, and inducing mitochondrial stress responses by suppressing the RAN-RRM2 axis. Concurrently, OSCC cells responded to cisplatin by upregulating and nuclear-localizing RRM2, thereby promoting pro-survival signaling. Functionally, RAN, a small GTPase, was critical for RRM2 nuclear localization and RRM2-mediated DNA repair, as demonstrated by GTP/GDP-locked mutants and RAN knockdown. Furthermore, rescue experiments using RRM2 and RAN constructs lacking miR-203a-3p-responsive 3'UTR sequences alleviate the chemosensitizing effects of miR-203a-3p, validating RRM2 and RAN as key downstream mediators. Altogether, our study demonstrates a miR-203a-3p/RRM2/RAN regulatory axis that modulates cisplatin response and provides insight into the molecular mechanisms underlying this process in OSCC.