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Gab2 expression in glioma and its implications for tumor invasion
Lihong Shi1, Xiuning Sun, Jin Zhang
1Department of Oncology, Nanfang Hospital of Southern Medical University , Guangzhou , PR China.
Abstract:
Gliomas are characterized by high invasiveness and poor prognosis. Better understanding of the mechanism of invasion in glioma cells is essential to the design of effective therapy. Recently Grb2-associated binder 2 (Gab2), a member of the DOS/Gab family of scaffolding adapters, has been reported to play important roles in the development and progression of human cancers. However, it is not known whether Gab2 has any role in the migration and invasion of gliomas. This study attempts to investigate the association between Gab2 expression and progression of gliomas and the molecular mechanism of Gab2 in the glioma cell invasion. Methods. The expression of Gab2 in pairs of matched glioma tissues and their normal brain tissues was detected by Western blot. Immunohistochemistry was applied to evaluate the expression of Gab2 in 163 cases of histologically diagnosed gliomas. The invasive character of Gab2 decreased glioma cells and control glioma cells were investigated in vitro and in vivo in SCID mice brain. Results. Gab2 is found to be high expressed in gliomas and a subset of cancer cell lines. Statistical analysis suggested that the up-regulation of Gab2 correlated with the WHO grade of gliomas (p < 0.01) and that patients with high Gab2 expression levels exhibited shorter survival time (p < 0.01). In an animal experiment, knockdown of Gab2 through siRNA inhibited invasive ability of glioma cells into the brain of SCID mice. In cell research, reduction of Gab2 by siRNA inhibits the migration and invasion of glioma cells by mediating cytoskeleton rearrangement and MMPs expression. Additionally, IGF-1-induced pAkt and pmTOR phosphorylation was suppressed by the knockdown of Gab2. Conclusion. Gab2 may be a useful prognostic marker for gliomas and a novel therapeutic target for glioma invasion intervention.
Insights
Grb2-associated binder 2 (Gab2) is highly expressed in gliomas, correlating with tumor grade and reduced survival. Gab2 inhibition suppressed glioma cell invasion, suggesting it as a therapeutic target.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Gliomas are highly invasive brain tumors with poor prognoses.
- Understanding glioma invasion mechanisms is crucial for developing effective therapies.
- Grb2-associated binder 2 (Gab2) is implicated in various human cancers but its role in gliomas is unknown.
Purpose of the Study:
- To investigate the association between Gab2 expression and glioma progression.
- To elucidate the molecular mechanisms underlying Gab2's role in glioma cell invasion.
Main Methods:
- Western blot and immunohistochemistry to assess Gab2 expression in glioma tissues.
- In vitro and in vivo (SCID mice) studies to evaluate glioma cell invasion with altered Gab2 levels.
- siRNA-mediated knockdown of Gab2 to assess its impact on cell migration, invasion, cytoskeleton, MMPs expression, and signaling pathways (Akt/mTOR).
Main Results:
- Gab2 was significantly upregulated in gliomas compared to normal brain tissue.
- High Gab2 expression correlated with higher WHO tumor grade and shorter patient survival.
- Gab2 knockdown inhibited glioma cell migration and invasion in vitro and in vivo.
- Gab2 reduction affected cytoskeleton rearrangement and matrix metalloproteinases (MMPs) expression.
- Gab2 knockdown suppressed IGF-1-induced phosphorylation of Akt and mTOR.
Conclusions:
- Gab2 is upregulated in gliomas and associated with aggressive disease.
- Gab2 plays a critical role in glioma cell invasion.
- Gab2 represents a potential prognostic marker and therapeutic target for glioma invasion.
