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Inhibition of GLI2 with antisense-oligonucleotides: A potential therapy for the treatment of bladder cancer

Peter A Raven1, Summer Lysakowski1, Zheng Tan1

  • 1Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.

Journal of Cellular Physiology
|April 24, 2019
PubMed

Insights

Targeting the sonic hedgehog (SHH) pathway with GLI2 antisense oligonucleotides (ASO) shows promise for bladder cancer (BCa) treatment. GLI2 ASO effectively reduced tumor growth and gene expression in preclinical models, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The sonic hedgehog (SHH) signaling pathway is implicated in bladder cancer (BCa) progression.
  • SHH pathway inhibition presents a potential therapeutic strategy for BCa.
  • GLI1 and GLI2, key SHH transcription factors, are upregulated during BCa progression.

Purpose of the Study:

  • To investigate the role of GLI1 and GLI2 in BCa progression.
  • To evaluate the efficacy of targeting GLI1 and GLI2 using antisense oligonucleotides (ASOs) in BCa.
  • To assess the therapeutic potential of GLI2 ASO in a preclinical BCa model.

Main Methods:

  • Analysis of SHH transcription factors (GLI1, GLI2) in human BCa tissues and cell lines.
  • Assessment of BCa cell line response to SHH pathway stimulation and inhibition.
  • Treatment of BCa cell lines with GLI1 and GLI2 ASOs.
  • Evaluation of GLI2 ASO efficacy in a murine intravesical orthotopic human BCa (mio-hBC) model.

Main Results:

  • GLI1 and GLI2 expression increased with BCa progression.
  • Differential responsiveness of BCa cell lines (UM-UC-3, 253J-BV) to SHH pathway modulators and ASOs was observed.
  • GLI2 ASO treatment in the mio-hBC model significantly reduced tumor size, growth rate, and GLI2 expression.

Conclusions:

  • GLI2 ASO demonstrates significant anti-tumor activity in preclinical BCa models.
  • Targeting GLI2 directly via ASO may represent a novel and effective therapeutic approach for bladder cancer.
  • Further investigation into GLI2 ASO as a targeted therapy for BCa is warranted.
Keywords:
GLI1GLI2antisense oligonucleotidebladder cancersonic hedgehog

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