Methyl-CpG Binding Protein 2 as a Potential Diagnostic and Prognostic Marker Facilitates Glioma Progression Through Activation of Wnt/β-Catenin Pathway

Abstract

Background: Glioma is the primary malignant tumor in the central nervous system and has high malignancy, mortality, and recurrence rates. Because of its heterogeneity and drug resistance, the blood-brain barrier, and other factors, the treatment of glioma has mainly been surgical resection combined with traditional radiotherapy and chemotherapy. However, the therapeutic effect has not been satisfactory. Methyl-CpG binding protein 2 (MeCP2) is an epigenetic regulator that has been reported to regulate the initiation and progression of glioma. However, the underlying mechanism in glioma has remained unclear.

Methods: The gene expression of MeCp2, miR-138-5p, the epithelial-mesenchymal transition, the apoptosis-related gene, and the Wnt/β-Catenin pathway-related gene and proliferation were detected by reverse transcription-quantitative polymerase chain reaction or Western blot. The cell proliferation and apoptosis of the glioma cell was assessed using the CCK-8 assay and flow cytometry assay. The relationship between miR-138-5p and MeCp2 was measured using the dual luciferase reporter assay. The effect of MeCp2 in U87 cells was examined in a xenograft tumorigenesis model in vivo.

Results: In our study, we found that MeCP2 was upregulated in glioma tissues and cell lines and that MeCP2 knockdown repressed cell proliferation and epithelial-mesenchymal transition but boosted cell apoptosis in glioma. Furthermore, MeCP2 knockdown attenuated in vivo glioma growth in a mice model. Mechanistically, miR-138-5p hindered the expression of MeCP2 by target MeCP2 and then inactivated the Wnt/β-catenin signaling pathway. In addition, subsequent rescue assays disclosed that miR-138-5p repressed the glioma malignant phenotype and MeCP2 overexpression reversed the inhibitory effect of miR-138-5p upregulation. Consistently, overexpression of MeCP2 elevated glioma development. However, inhibition of the Wnt/β-catenin signaling pathway with XAV-939 rescued the facilitation effect by overexpressing miR-138-5p.

Conclusions: Our results have revealed that miR-138-5p/MeCP2/Wnt/β-catenin signaling might be a new target axis for glioma treatment strategies.

Keywords: EMT; Glioma; MeCP2; Proliferation; Wnt/β-catenin.