MiR-1253 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Regulating Ferroptosis

Abstract

AbstractMedulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Patients with group 3 tumors have the poorest prognosis. Loss of 17p13.3, which houses the tumor suppressor gene miR-1253, is a frequent high-risk feature of group 3 tumors.. In this study, we show that miR-1253 levels can disrupt iron homeostasis, induce oxidative stress and lipid peroxidation, triggering an iron-mediated form of cell death called ferroptosis. In silico and in vitro analyses of group 3 tumors revealed deregulation of ABCB7, a mitochondrial iron transporter and target of miR-1253, and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 levels in group 3 cell lines resulted in downregulation of ABCB7 and GPX4, consequently increasing cytosolic and mitochondrial labile iron pools, reducing glutathione levels, in turn, resulting in mitochondrial oxidative stress and lipid peroxidation. Together, these events accelerated cancer cell death. Treating miR-1253-expressing cancer cells with cisplatin potentiated cell death by further elevating oxidative stress, depleting glutathione levels, and augmenting lipid peroxidation, with added inhibitory effects on cell viability and colony formation. Treatment with a ferroptosis inhibitor (ferrostatin-1) lead to recovery from the cytotoxic effects of this combination therapy. Together, these findings reveal a novel role for miR-1253 in enhancing ferroptosis to attenuate group 3 tumor cell growth. Our studies provide a proof-of-concept for using miR-based therapeutics to augment current chemotherapeutics in high-risk tumors. Leveraging the tumor-suppressive properties of miRNAs as adjuncts to chemotherapy may provide a promising alternative to current therapeutic strategies.