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Abstract: Glioblastoma stem cells (GSCs) play an important role in the progression and recurrence of malignant glioblastoma because of their potential for self-renewal, multilineage differentiation and tumor initiation. A disintegrin and metalloproteinase 17 (ADAM17) is responsible for the proteolytic cleavage of Notch within its extracellular domain leading to the activation of Notch signaling, which is involved in the formation and maintenance of GSCs. Here, we show that glioma cells expressing the stem cell marker CD133 coexpress higher levels of ADAM17 than matched CD133-glioma cells. Knockdown of the ADAM17 gene in U87 GSCs down-regulated the expression of CD133, inhibited secondary neurosphere formation and induced multi-lineage differentiation. Furthermore, knockdown of ADAM17 inhibited Hes1 and Hes5 and activated Notch1 expression, which may explain the ADAM17 shRNA-induced suppression of self-renewal and differentiation of U87 GSCs. Our results suggest that ADAM17 may maintain the stemness of GSCs by promoting their self-renewal and inhibiting their differentiation via Notch signaling. [Copyright &y& Elsevier]