Role of MBNL1/circNTRK/PAX5 Pathway in Inhibiting Glioblastoma Cells Aerobic Glycolysis via Encoding a Novel Protein NTRK2-243aa

Researchers have found that RNA-binding proteins (RBPs) and circular RNAs (circRNAs) are dysregulated in tumors and play crucial roles in the development and progression of tumors. By analyzing the data of The Cancer Genome Atlas (TCGA) and our experimental findings, we screened the tumor suppressor MBNL1 (muscleblind like splicing regulator 1), and circRNA microarray was used to screen circNTRK2. Further, the transcription factor PAX5 (paired box 5) was selected as a research candidate by correlation analysis. In this study, MBNL1 and circNTRK2 were markedly downregulated, while PAX5 was highly expressed in glioblastoma multiforme (GBM). Moreover, gain and loss-of-function assays indicated that MBNL1 or circNTRK2 significantly abrogated, while PAX5 promoted, glycolysis and proliferation of GBM cells. MBNL1 may promote the cyclization of circNTRK2 by binding to NTRK2 pre-mRNA. Importantly, NTRK2-243aa encoded by circNTRK2 phosphorylated PAX5 at Y102 leading to half-life of PAX5 protein attenuating. Besides, PAX5 could transcriptionally faciltate the expression of PKM2 (pyruvate kinase M2) and HK2 (hexokinase 2) by binding to their promoter regions. Furthermore, in vivo experiments confirmed that MBNL1 and circNTRK2 could suppress tumor growth while PAX5 imped. In conclusion, our study revealed that the MBNL1/circNTRK2/PAX5 pathway regulated glycolysis and proliferation of GBM cells via encoding a novel protein NTRK2-243aa, which may provide a new strategy for targeted therapy of GBM.