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Interruption of β-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells
Xiao Yue1, FengMing Lan, WeiDong Yang
1Laboratory of Neuro-Oncology, Tianjin Neurological Institute, PR China.
Abstract:
Malignant gliomas are the most common type of intrinsic central nervous system (CNS) tumors with high mortality and morbidity. β-catenin is overexpressed in human glioblastoma and knockdown of β-catenin inhibits glioblastoma cell proliferation and invasive ability, and induces apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous LN229 gliomas with siRNA targeting β-catenin intratumorally also delayed the tumor growth. However, the mechanisms of down-regulation of β-catenin that represses glioblastoma malignancy behavior remain to be elucidated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the β-catenin biologic association network, and identified several interactions of this network with the EGFR pathway. In both in vitro and in vivo studies, our results confirmed down-regulation of β-catenin induced reduced expression of EGFR, STAT3 and AKT1 mRNA and protein, besides, the level of phosphorylated Akt also decreased. A similar reduction in expression of CyclinD1, MMP2 and MMP9, downstream genes of the EGFR pathway, was observed. These results suggest that the Wnt/β-catenin pathway regulates glioma cell proliferation and invasion, in part via the EGFR pathway.
Insights
Targeting beta-catenin (β-catenin) in malignant gliomas inhibits tumor growth and invasion. This study reveals beta-catenin regulates glioma malignancy partly through the EGFR pathway, offering new therapeutic targets.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Malignant gliomas are aggressive brain tumors with poor outcomes.
- Overexpression of β-catenin is linked to glioblastoma progression.
- Previous studies show β-catenin knockdown inhibits glioblastoma growth and invasion.
Purpose of the Study:
- To elucidate the mechanisms by which β-catenin down-regulation suppresses glioblastoma malignancy.
- To investigate the interaction between the Wnt/β-catenin pathway and the EGFR pathway in glioma.
Main Methods:
- Text-mining of MEDLINE abstracts using natural language processing to build the β-catenin biologic association network.
- In vitro and in vivo studies involving siRNA targeting β-catenin in glioblastoma models.
- Analysis of gene and protein expression of key pathway components (EGFR, STAT3, AKT1, CyclinD1, MMP2, MMP9).
Main Results:
- Down-regulation of β-catenin reduced the expression of EGFR, STAT3, and AKT1 mRNA and protein.
- Phosphorylated Akt levels were decreased following β-catenin knockdown.
- Expression of downstream EGFR pathway genes, including CyclinD1, MMP2, and MMP9, was also reduced.
Conclusions:
- The Wnt/β-catenin pathway plays a significant role in regulating glioma cell proliferation and invasion.
- This regulation is, in part, mediated through interactions with the EGFR pathway.
- Targeting β-catenin may represent a viable therapeutic strategy for malignant gliomas.
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