ISL1 promotes human glioblastoma-derived stem cells self-renewal by activation of SHH/GLI1 function.

Abstract

Glioblastoma, the most aggressive primary heterogeneous primary brain tumor, is a glioma subtype of glioma that originates from the glial cells of the central nervous system. Glioblastoma stem cells (GSCs), situated at the top of the hierarchy, initiate and maintain the tumor and are largely accountable for glioblastoma resistance to the mainstay treatment and recurrence. The LIM homeobox transcription factor islet1(ISL1) induces tumorigenicity in various tumors; however, its function in GSCs has been less reported. We aimed to generate GSCs from surgical specimens of human glioblastoma and investigate the effect of ISL1 knockdown on GSCs. We established patient derived GSCs, determined cancer stem cell marker expression, and immunostained GSCs to assess cell viability and apoptosis. We demonstrated that ISL1 deletion decreased the GSC viability and proliferation, and upregulated apoptosis. Moreover, we performed enzyme-linked immunosorbent assay and western blotting and found that ISL1 knockdown affected the expression of sonic hedgehog (SHH) and its downstream regulator GLI1, and further validated these results by supplementing the cells with recombinant SHH. Our results suggested that ISL1 played a critical role in regulating GBM growth and that an ISL1/SHH/GLI1 pathway was required for the maintenance of GBM progression and malignancy. The regulation of GSC growth via ISL1 might be a mechanism of interest for future therapeutic studies.