targeting a20 decreases glioma stem cell survival and tumor growth针对a20减少神经胶质瘤干细胞生存和肿瘤的生长.pdfVIP

Targeting A20 Decreases Glioma Stem Cell Survival and Tumor Growth 1 1 2 1,2 1 2 Anita B. Hjelmeland *, Qiulian Wu , Sarah Wickman , Christine Eyler , John Heddleston , Qing Shi , 1 1 1 3 1 Justin D. Lathia , Jennifer MacSwords , Jeongwu Lee , Roger E. McLendon , Jeremy N. Rich * 1 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 2 Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America, 3 Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America Abstract Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFa-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GS