GLI1 is involved in HIF-1?-induced migration, invasion, and epithelial-mesenchymal transition in glioma cells

Introduction. Glioma is characterized by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive cancer progression. HIF-1 alpha promotes GLI1 transferring to the nucleus by activating the hedgehog pathway under hypoxic conditions. However, their mechanisms in glioma cells under hypoxia remain unknown. Material and methods. Human glioma cell lines (LN229 and LN18) were transfected with HIF-1 alpha or GLI1-specific short hairpin RNAs (shRNAs) and cultured under normoxic or hypoxic conditions. The protein levels of HIF-1 alpha, GLI1, and epithelial-mesenchymal transition (EMT) markers including E-cadherin and vimentin were measured by Western blot analysis. RT-qPCR analysis was performed for the detection of HIF-1 alpha and GLI1 mRNA expression. Cell migratory and invasive capacities were evaluated by wound healing and Transwell assays, respectively. Results. Hypoxia blocked the breakdown of the HIF-1 alpha protein and upregulated GLI1 expression in glioma cells. Downregulation of HIF-1 alpha expression inhibited hypoxia-induced cell migration and invasion, as well as reversed the effects of hypoxia on GLI1, E-cadherin, and vimentin expression in LN229 and LN18 cells. Depletion of GLI1 inhibited glioma cell migration and invasion induced by hypoxia. Silenced GLI1 did not affect HIF-1 alpha expression but completely offset hypoxia-regulated expression of E-cadherin and vimentin in glioma cells. Conclusions. GLI1 is involved in HIF-1 alpha-induced migration, invasion, and EMT in glioma cells, thus revealing a novel molecular mechanism for glioma research. (Folia Histochemica et Cytobiologica 2022, Vol. 60, No. 2, 156-166)