The GLI1 splice variant TGLI1 promotes glioblastoma angiogenesis and growth

• TGLI1 transcripts and encoded protein were highly expressed in approximately half of the GBM specimens we have analyzed.
• TGLI1-expressing GBM xenografts grow larger and present with greater tumor angiogenesis than GLI1-expressing GBM tumors.
• The heparanase-1 (HPA1) gene is a novel transcriptional target of TGLI1.
• TGLI1–associated upregulation of HPA1 and VEGF-A contributes to the excessive vascularity of GBM.
• The study helps define TGLI1 as a novel mediator of growth and angiogenesis of GBM.

We investigated truncated glioma-associated oncogene homolog 1 (TGLI1) that behaves as gain-of-function GLI1 and promotes tumor cell migration and invasion. Herein, we report that TGLI1 had a higher propensity than GLI1 to enhance glioblastoma angiogenesis and growth, both in vivo and in vitro. TGLI1 has gained the ability to enhance expression of pro-angiogenic heparanase. In patient glioblastomas, TGLI1 levels are correlated with heparanase expression. Together, we report that TGLI1 is a novel mediator of glioblastoma angiogenesis and that heparanase is a novel transcriptional target of TGLI1, shedding new light on the molecular pathways that support tumor angiogenesis and aggressive growth.