A Circular RNA Drives Glioblastoma Invasion through Enhancing YBX1-Mediated ADAMTS5 Translation

Glioblastoma (GBM) is characterized by aggressive invasiveness, with the role of circular RNAs (circRNAs) in this process remains unknown. Here, we identify circMETTL3 as a key regulator of GBM invasion through analyzing the core and invasive margin cells from patient samples and animal models. circMETTL3 is significantly upregulated in GBM tumors compared to normal tissues and enhances invasiveness in vitro and in vivo. Mechanistically, circMETTL3 selectively binds to the 5'UTR of invasion-related mRNAs, such as ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), promoting ADAMTS5 translation in a Y-box-binding protein 1 (YBX1)-dependent manner, thereby driving GBM migration and invasion. Furthermore, elevated circMETTL3 correlates with higher ADAMTS5 expression, increased GBM invasion and poor survival of GBM patients. Therefore, these findings highlight the substantial role of circMETTL3 in accelerating GBM malignancy through regulating translation of certain mRNAs, underscoring its potential as a prospective biomarker and therapeutic target for GBM.