CircRNAs are dysregulated in various cancers, where they mediate cellular proliferation, migration, and invasion. CircRNAs can regulate gene expression and translation by sponging RNA-binding proteins and microRNAs (miRNA, miR) and, in some cases, generating a protein through translation. Therefore, circRNAs are resistant to degradation by RNases and are abundant in mammalian cells and body fluids, providing opportunities for non-invasive sampling for biomarker analysis. CircRNAs are generated from pre-messenger RNA via back-splicing, where the 3′ and 5′ ends are connected via a covalent bond to form a loop structure devoid of a 5′ cap and 3′ poly(A) tail. In addition, circRNAs are abundant in the mammalian brain, so they may be perfect candidates for biomarkers in medulloblastoma. CircRNAs are now established as pathogenic in various cancers and have potential as diagnostic or therapeutic targets. CircRNAs are exceptionally stable and generally cytoplasmic. Ĭircular RNAs (circRNAs) have recently emerged as a class of endogenous tissue- and developmental stage-specific ncRNAs. We recently identified significant heterogeneity in long non-coding RNAs (lncRNAs) in MBs by molecular subgroup, with lnc-HLX-2-7 oncogenic in Group 3 (G3) MBs and Sprightly in Group 4 (G4) MBs. Noncoding (nc) RNAs-which represent most of the transcribed genome-may be useful for sub-stratifying MBs. Fully defining medulloblastoma heterogeneity requires an approach that goes beyond characterizing individual genes, since cancer development represents the product of complex interactions in and between signaling networks and their regulation. Recent studies have identified several medulloblastoma subgroup-specific biomarkers and molecular targets including oncogenes and tumor suppressor genes such as MYCN, MYC, TP53, CDK6, ALK, GLI1, SNCAIP, OTX2, and SNCA. There is a compelling clinical need for novel molecular markers and therapeutic targets for specific molecular subgroups to improve outcomes. However, their degree of overlap, underlying genetics and biology, and intrinsic diversity have yet to be fully identified, despite a need to define individual tumors for targeted therapy. Many studies have discovered reliable molecular markers for these subgroups. Advances in next‐generation sequencing and genome‐wide association analyses have unraveled significant heterogeneity in medulloblastoma, such that the World Health Organization Classification of Tumors of the Nervous System has for some time classified MBs into molecular subgroups: wingless (WNT)-activated, sonic hedgehog (SHH)-activated and TP53 wildtype, SHH-activated and TP53 mutant, and non-WNT/non-SHH. Approximately 500 patients are diagnosed with medulloblastoma in the United States each year, of whom 60% are children under fifteen. Medulloblastoma (MB) is a highly malignant childhood brain tumor accounting for ~ 20% of all pediatric brain tumors and 63% of intracranial embryonic tumors. Our study implicates a novel oncogenic circular RNA in the SHH medulloblastoma subgroup and establishes its molecular function and potential as a future therapeutic target. At the molecular level, circ_63706-deleted cells elevated total ceramide and oxidized lipids and reduced total triglyceride. circ_63706-deleted cells implanted into mice produced smaller tumors, and mice lived longer than parental cell implants. Circ_63706 regulates independently of the host coding gene pericentrin ( PCNT), and its expression is specific to the SHH subgroup. Finally, we mapped the circ_63706 secondary structure using an advanced random forest classification model and modeled a 3D structure to identify its interacting miRNA partner molecules. Further, circ_63706-depleted cells were subjected to RNA-seq and lipid profiling to identify its molecular function. The oncogenic function of circ_63706 was characterized in vitro and in vivo. circ_63706 was identified as sonic hedgehog (SHH) group-specific, with its expression confirmed by RNA-FISH analysis in clinical tissue samples. To determine medulloblastoma subgroup-specific circRNAs, publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify circRNAs that differentiate between MB subgroups. CircRNAs are increasingly recognized as stable non-coding RNA therapeutic targets in many cancers, but little is known about their function in MBs. Medulloblastoma (MB) develops through various genetic, epigenetic, and non-coding (nc) RNA-related mechanisms, but the roles played by ncRNAs, particularly circular RNAs (circRNAs), remain poorly defined.
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