Downregulation of Wnt2 and β-catenin by siRNA suppresses malignant glioma cell growth

Abstract

Increasing evidence suggests that aberrant activation of Wnt signaling is involved in tumor development and progression. Our earlier study on gene expression profile in human gliomas by microarray found that some members of Wnt family were overexpressed. To further investigate the involvement of Wnt signaling in gliomas, the expression of core components of Wnt signaling cascade in 45 astrocytic glioma specimens with different tumor grades was examined by reverse transcription-PCR and immunohistochemistry. Wnt2, Wnt5a, frizzled2 and beta-catenin were overexpressed in gliomas. Knockdown of Wnt2 and its key mediator beta-catenin in the canonical Wnt pathway by siRNA in human U251 glioma cells inhibited cell proliferation and invasive ability, and induced apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous U251 gliomas with siRNA targeting Wnt2 and beta-catenin intratumorally also delayed the tumor growth. In both in vitro and in vivo studies, downregulation of Wnt2 and beta-catenin was associated with the decrease of PI3K/p-AKT expression, indicating the interplay between Wnt/beta-catenin and PI3K/AKT signaling cascades. In conclusion, the canonical Wnt pathway is of critical importance in the gliomagenesis and intervention of this pathway may provide a new therapeutic approach for malignant gliomas.

Expression profile and clinical significance of Wnt signaling in human gliomas

“…Although the expression of Wnt/β-catenin signaling pathway members in glioma has been demonstrated previously (15,(18)(19)(20), there is a lack of studies that have systematically investigated the expression of Wnt signaling. In order to comprehensively characterize the expression of Wnt signaling in glioma tissues, the R2: Genomics Analysis and Visualization Platform database was interrogated, which revealed that, in patients with glioma, the median mRNA expression levels of Wnt2b, Wnt5a, FZD1-7 were increased compared with other Wnt pathway members (Fig.…”

“…Thus, the mRNA expression levels of Wnt ligands, receptors, β-catenin destruction complex and its target genes cyclin D1 and AXIN2 were determined using qPCR. Based on previous studies, which detected the Wnt ligands in glioma cells and tissues (15,18), eight members of the Wnt family (Wnt2b, 3, 3a, 5a, 5b, 7b, 9b and 11) were selected for further investigation. As presented in Fig.…”

Brain tumor stem cells: phenotypic characterization and directed therapeutic approaches

“…The in vitro and in vivo experiments, using siRNA for Wnt2 and β-catenin, have demonstrated inhibition of cell proliferation and invasion as well as inhibition of tumor development. Furthermore, suppression of Wnt2 and β-catenin is associated with reduced PI3K/Akt expression that is associated with an interaction between Wnt/β-catenin and PI3K/Akt signal cascades [59]. Expression of CD133 and Wnt-1 is elevated in the stem cells isolated from the glioblastomas.…”

Genome-wide identification of TCF7L2/TCF4 target miRNAs reveals a role for miR-21 in Wnt-driven epithelial�cancer

“…This complex regulates transcription of multiple genes involved in cellular proliferation, differentiation, survival and apoptosis, including Fra-1, c-myc and Cyclin D. In the past, our group has demonstrated that Wnt/β-catenin/TCF signaling was significantly dysregulated in gliomas and down-regulated β-catenin/ TCF signaling which can inhibit cell proliferation and invasive ability, induced apoptotic cell death (23). Furthermore, we clarified that down-regulation of β-catenin/TCF signaling inhibited several members of the EGFR pathway in human glioma cells (24).…”