WNT/β-catenin Signaling Pathway and Downstream Modulators in Low- and High-grade Glioma

Background: Aberrant activation of the canonical Wingless-type MMTV integration site family (WNT)/beta-catenin signaling pathway is critical for gliomas. Materials and Methods: In 74 gliomas of different histological grade and in 24 glioblastoma cell lines, protein expression of WNT member 3a (WNT3a), beta-catenin and transcription factor 4 (TCF4) was investigated by immunohistochemistry, western blotting, immunofluorescence and immunocytochemistry. In tumors and cell lines, WNT3A expression was assessed at the mRNA level by quantitative real-time polymerase chain reaction. Results: WNT3a was overexpressed at the protein and mRNA levels in malignant astrocytic tumors and cell lines. Cytoplasmic expression of beta-catenin was detected in high-grade gliomas and cell lines, with evidence of nuclear translocation on fractionated protein extracts. Activating mutations in the beta-catenin encoding gene (CTNNB1) were excluded by direct sequencing. TCF4 was statistically correlated with Ki-67/MIB-1 and cyclin D1 labeling indices. Conclusion: Expression of WNT3a, cytoplasmic beta-catenin and TCF4 was significantly associated with the histological malignancy grade and with a worse prognosis for patients with glioma.