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3-D Cell Culture System for Studying Invasion and Evaluating Therapeutics in Bladder Cancer
Published on: September 13, 2018
Loss of GATA3 in bladder cancer promotes cell migration and invasion
Yi Li1, Hitoshi Ishiguro2, Takashi Kawahara2
1Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester, NY USA; Department of Urology; 2nd Affiliated Hospital; Zhejiang University School of Medicine; Hangzhou, PR China.
Abstract:
The transcription factor GATA3 is known as a breast tumor suppressor as well as a urothelial marker, and its loss is often seen in high-grade invasive bladder cancer. Nonetheless, GATA3 functions in bladder cancer cells remain largely unknown. In this study, we assessed the effects of GATA3 silencing via RNA interference on cell migration, invasion, and proliferation of bladder cancer. GATA3 expression was downregulated in all four bladder cancer lines examined, compared with a non-neoplastic urothelial line SVHUC. Knockdown of GATA3 in the bladder cancer lines (5637, TCC-SUP, J82) resulted in promotion of cell migration and invasion as well as increases in the expression of their related molecules, such as vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9, and the activity of MMP-2 and MMP-9. GATA3 loss was also associated with an increasing level of a mesenchymal marker N-cadherin and a decreasing level of an epithelial marker β-catenin. Consistent with these findings, enforced expression of GATA3 in UMUC3 inhibited cell migration and invasion. However, GATA3 showed marginal effects on bladder cancer cell viability and the expression of cell cycle- or apoptosis-related molecules. Additionally, in contrast to bladder cancer lines, no significant effects of GATA3 silencing on cell migration were seen in SVHUC. These findings suggest that GATA3 plays an important role in the prevention of bladder cancer progression and metastasis by inhibiting cell migration and invasion as well as epithelial-to-mesenchymal transition.
Insights
Loss of the transcription factor GATA3 promotes bladder cancer progression by increasing cell migration and invasion. GATA3 acts as a tumor suppressor, inhibiting metastasis and epithelial-to-mesenchymal transition in bladder cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- GATA3 is a transcription factor known as a breast tumor suppressor and urothelial marker.
- Loss of GATA3 expression is frequently observed in high-grade invasive bladder cancer.
- The specific functions of GATA3 within bladder cancer cells are not well understood.
Purpose of the Study:
- To investigate the functional role of GATA3 in bladder cancer progression.
- To assess the impact of GATA3 silencing on key cancer cell behaviors like migration, invasion, and proliferation.
- To explore the molecular mechanisms underlying GATA3's function in bladder cancer.
Main Methods:
- Utilized RNA interference (RNAi) to silence GATA3 expression in bladder cancer cell lines.
- Quantified changes in cell migration and invasion assays.
- Analyzed the expression and activity of key molecules involved in metastasis, including vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), N-cadherin, and β-catenin.
- Performed experiments with enforced GATA3 expression in a bladder cancer cell line.
Main Results:
- GATA3 expression was significantly downregulated in multiple bladder cancer cell lines compared to normal urothelial cells.
- GATA3 knockdown led to increased cell migration and invasion, accompanied by elevated expression and activity of MMP-2 and MMP-9, and vascular endothelial growth factor.
- GATA3 loss correlated with increased N-cadherin and decreased β-catenin, indicating promotion of epithelial-to-mesenchymal transition (EMT).
- Enforced GATA3 expression suppressed migration and invasion, while GATA3 had minimal impact on cell viability, proliferation, cell cycle, or apoptosis.
- Silencing GATA3 did not significantly affect migration in normal urothelial cells.
Conclusions:
- GATA3 functions as a suppressor of bladder cancer progression and metastasis.
- GATA3 inhibits bladder cancer cell migration, invasion, and epithelial-to-mesenchymal transition.
- GATA3's tumor-suppressive role in bladder cancer is primarily mediated through the regulation of cell motility and EMT, rather than direct effects on proliferation or apoptosis.
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