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Published on: May 1, 2015
PEA3 Transcription Factors, Role in Invasion, Proliferation and Radioresistance of Glioblastoma Stem Cells
Yvan Nicaise1, Caroline Delmas1,2, Elizabeth Cohen-Jonathan-Moyal1,2
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III-Paul Sabatier, Toulouse, France.
Abstract:
The presence of glioblastoma stem cells (GSCs), known for their high invasiveness and resistance to radiation, is one of the reasons for systematic recurrence. It is therefore important to understand the resistance mechanisms of these cells to optimise therapies. We focused on the PEA3 family of transcription factors, ETV1, ETV4 and ETV5, in patient-derived GSCs. We demonstrate that ETV1 is over-expressed in high invasive GSCs. In 3D invasion assays, inhibiting ETV1 expression using specific siRNAs significantly reduces cell invasion. Furthermore, we show a significant correlation between ETV1 and ZEB1, a major driver of invasion. Blocking ETV1 decreases ZEB1 expression in GSCs. The study also demonstrates the essential role of ETV1, ETV4 and ETV5 in the radioresistance of GSCs and their ability to form neurospheres. Using specific siRNAs to inhibit the expression of these transcription factors led to an increased sensitivity of GSCs to radiation and a decrease in both the number and size of neurospheres. These findings suggest that PEA3 transcription factors play a major role in GSCs aggressiveness by regulating invasion, radioresistance and the ability to form neurospheres. Trial Registration: Registry and the Registration N° of the study/trial: 12TETE01, ID-RCB No. 2012-A00585-38, approval Date: May 7, 2012.
Insights
Glioblastoma stem cells (GSCs) resist radiation and invade tissues. Targeting PEA3 transcription factors like ETV1, ETV4, and ETV5 may overcome GSC resistance and invasion, improving glioblastoma treatment outcomes.
Area of Science:
- Neuro-oncology
- Cancer stem cell biology
- Molecular mechanisms of cancer progression
Background:
- Glioblastoma stem cells (GSCs) drive tumor recurrence due to invasiveness and radioresistance.
- Understanding GSC resistance mechanisms is crucial for developing effective glioblastoma therapies.
Purpose of the Study:
- To investigate the role of PEA3 family transcription factors (ETV1, ETV4, ETV5) in GSC invasion, radioresistance, and neurosphere formation.
- To explore the therapeutic potential of targeting these factors in glioblastoma.
Main Methods:
- Utilized patient-derived GSCs.
- Employed 3D invasion assays and siRNA-mediated gene silencing.
- Assessed GSC radioresistance and neurosphere formation capacity.
- Correlated ETV1 expression with ZEB1, a known invasion driver.
Main Results:
- ETV1 is overexpressed in highly invasive GSCs and its inhibition significantly reduces invasion.
- ETV1 inhibition decreases ZEB1 expression, a key invasion driver.
- ETV1, ETV4, and ETV5 are essential for GSC radioresistance and neurosphere formation.
- Inhibiting PEA3 factors increased GSC sensitivity to radiation and reduced neurosphere formation.
Conclusions:
- PEA3 transcription factors (ETV1, ETV4, ETV5) are critical regulators of glioblastoma stem cell aggressiveness.
- Targeting PEA3 factors offers a promising strategy to enhance glioblastoma treatment efficacy by reducing invasion and overcoming radioresistance.
