lncRNAs and circRNAs: Emerging Players in Pediatric Medulloblastoma Pathology

Medulloblastomas (MBs) are the most common malignant brain tumors in children, marked by aggressive growth, molecular heterogeneity, and a high propensity for cerebrospinal dissemination. Despite advancements in conventional treatments - surgery, chemotherapy, and radiation therapy—substantial challenges persist, including debilitating long-term toxicities and emerging resistance to therapy. This review examines the multifaceted roles of non-coding RNAs (ncRNAs) - particularly long non- coding RNAs (lncRNAs) and circular RNAs (circRNAs) - in pediatric medulloblastoma pathogenesis, diagnosis, and therapeutic targeting. NcRNAs exert robust regulatory effects on gene expression by modulating signaling pathways, acting as miRNA sponges, and controlling the expression of oncogenic or tumor-suppressive genes. In this study, we focus on notable examples of lncRNAs (e.g., HOTAIR, TP73-AS1) and circRNAs (e.g., circ-SKA3, circ_63706) implicated in fundamental oncogenic processes, such as cell proliferation, apoptosis, metastasis, and stem cell maintenance. We also discuss their subgroup-specific roles, emphasizing high-risk groups, such as Sonic Hedgehog (SHH) and Group 3 medulloblastomas. In parallel, we explore the potential of ncRNAs to serve as diagnostic/prognostic biomarkers, given their tissue-specific expression, stability, and detectability in biological fluids like the Cerebrospinal Fluid (CSF). Finally, we review emerging therapeutic strategies, including antisense oligonucleotides, RNA sponges, and CRISPR-based editing, aimed at disrupting oncogenic ncRNA functions or reinforcing tumor-suppressive pathways. While these strategies hold promise, major hurdles include functional redundancy, optimizing in vivo delivery, and mitigating off-target effects. By detailing these challenges and outlining future research directions, this review underscores the revolutionary potential of ncRNA-focused diagnostics and therapies for managing pediatric medulloblastomas, offering new paths for improving survival outcomes and quality of life in affected children. © 2025 Elsevier B.V., All rights reserved.