The oncogenic circular RNA circ_63706 is a potential therapeutic target in sonic hedgehog-subtype childhood...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Medulloblastoma (MB) is a complex brain tumor with poorly understood roles for non-coding RNAs (ncRNAs).
• Circular RNAs (circRNAs), a class of ncRNAs, are emerging as potential therapeutic targets in cancer, but their function in MB is largely unknown.

Purpose of the Study:

• To identify medulloblastoma subgroup-specific circRNAs.
• To characterize the function and molecular mechanisms of a novel circRNA, circ_63706, in the sonic hedgehog (SHH) MB subgroup.

Main Methods:

• RNA sequencing (RNA-seq) analysis of 175 MB patient samples to identify subgroup-specific circRNAs.
• RNA fluorescence in situ hybridization (RNA-FISH) for expression validation.
• In vitro and in vivo functional assays (cell depletion, tumor implantation in mice).
• RNA-seq and lipid profiling of circRNA-depleted cells.
• Bioinformatic analysis including random forest classification for secondary structure mapping and 3D modeling.

Main Results:

• Identified circ_63706 as specific to the SHH MB subgroup, independent of its host gene PCNT.
• Depletion of circ_63706 significantly reduced tumor growth in vivo and prolonged mouse survival.
• Molecular analysis revealed circ_63706 depletion altered lipid metabolism, increasing ceramides and oxidized lipids while decreasing triglycerides.
• Mapped circ_63706 secondary structure and modeled its 3D structure to predict miRNA interactions.

Conclusions:

• Circ_63706 is a novel oncogenic circRNA in the SHH medulloblastoma subgroup.
• Circ_63706 plays a critical role in MB tumorigenesis and influences lipid metabolism.
• Circ_63706 represents a promising therapeutic target for SHH medulloblastoma.