The Role Played by SLUG, an Epithelial-Mesenchymal Transition Factor, in Invasion and Therapeutic Resistance of Malignant Glioma.

Abstract

In malignant gliomas, invasive phenotype and cancer stemness promoting resurgence of residual tumor cells render treatment very difficult. Hence, identification of epithelial-mesenchymal transition (EMT) factors associated with invasion and stemness of glioma cells is critical. To address the issue, we investigated several EMT factors in hypermotile U87MG and U251 cells, orthotopic mouse glioma model, and human glioma samples. Of several EMT markers, SLUG expression was notably increased at the invasive fronts of gliomas, both in mouse tumor grafts and human glioma samples. The biological role played by SLUG was investigated using a colony-forming assay after chemotherapy and irradiation, and by employing a neurosphere culture assay. The effect of SLUG on glioma progression was examined in our patient cohort and samples, and compared to large public data from the REMBRANDT and TCGA. Genetic upregulation of SLUG was associated with increased levels of stemness factors and enhanced resistance to radiation and temozolomide. In our cohort, patients exhibiting lower-level SLUG expression evidenced longer progression-free survival (P = 0.042). Also, in the REMBRANDT dataset, a group in which SLUG was downregulated exhibited a significant survival benefit (P < 0.001). Although paired glioblastoma samples from our patients did not show a significant increase of SLUG expression, increased mRNA levels of SLUG were found in recurrent glioblastoma from TCGA (P = 0.052), and in temozolomide-treated glioma cells and mouse tumor grafts. SLUG may contribute to glioma progression by controlling invasion at infiltrating margins, associated with increased stemness and therapeutic resistance.