ADAM17 Confers Temozolomide Resistance in Human Glioblastoma Cells and miR-145 Regulates Its Expression

Abstract

Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.