Inhibition Of Gli2 With Antisense-Oligonucleotides: A Potential Therapy For The Treatment Of Bladder Cancer

The sonic hedgehog (SHH) signaling pathway plays an integral role in the maintenance and progression of bladder cancer (BCa) and SHH inhibition may be an efficacious strategy for BCa treatment. We assessed an in-house human BCa tissue microarray and found that the SHH transcription factors, GLI1 and GLI2, were increased in disease progression. A panel of BCa cell lines show that two invasive lines, UM-UC-3 and 253J-BV, both express these transcription factors but UM-UC-3 produces more SHH ligand and is less responsive in viability to pathway stimulation by recombinant human SHH or smoothened agonist, and less responsive to inhibitors including the smoothened inhibitors cyclopamine and SANT-1. In contrast, 253J-BV was highly responsive to these manipulations. We utilized a GLI1 and GLI2 antisense oligonucleotide (ASO) to bypass pathway mechanics and target the transcription factors directly. UM-UC-3 decreased in viability due to both ASOs but 253J-BV was only affected by GLI2 ASO. We utilized the murine intravesical orthotopic human BCa (mio-hBC) model for the establishment of noninvasive BCa and treated tumors with GLI2 ASO. Tumor size, growth rate, and GLI2 messenger RNA and protein expression were decreased. These results suggest that GLI2 ASO may be a promising new targeted therapy for BCa.