TRIM24 promotes stemness and invasiveness of glioblastoma cells via activating Sox2 expression
TRIM24 promotes stemness and invasiveness of glioblastoma cells via activating Sox2 expression
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TRIM24通过激活Sox2表达促进胶质母细胞瘤细胞的干性和侵袭性
DOI：
10.1093/neuonc/noaa138
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发表时间：
2020-12-01
期刊：
影响因子：
15.9
通讯作者：
Xu, Dong-gang
中科院分区：
文献类型：
--
作者：
Zhang, Lu-hua;Yin, Yi-heng;Xu, Dong-gang
背景资料。胶质母细胞瘤干细胞(GSCs)是胶质母细胞瘤(GBM)细胞的一个亚群，对肿瘤的侵袭和治疗耐药起关键作用。然而，含三个基序的24个基序(TRIM24)在GSC中的功能和机制却鲜为人知。免疫荧光、流式细胞术和免疫印迹分析检测TRIM24和分化簇(CD)133在GBM手术标本和GSC肿瘤球中的表达。免疫组织化学和免疫印迹法检测患者肿瘤中不同的TRIM24表达水平与其相应的MRI数据相关。通过伤口愈合、Matrigel侵袭和异种移植免疫组织化学方法确定GBM细胞的侵袭。我们发现TRIM24与CD133和Nestin在基底膜组织和肿瘤细胞中共表达。极限稀释实验和异种移植实验表明，下调TRIM24的表达降低了GSC的自我更新能力和侵袭性生长。TRIM24表达水平与瘤周T2加权像异常体积呈正相关。救援实验表明，TRIM24参与了GBM的浸润性传播。染色质免疫沉淀、报告基因分析、聚合酶链式反应、免疫印迹和免疫组织化学结果表明，TRIM24可激活多能转录因子性别决定区Y-box 2(Sox2)的表达，从而调节GBM的干性和体内外侵袭。最后，通过对研究样本的测试和对外部数据库的探索，验证了TRIM24与SOX2的密切关系。我们的发现揭示了TRIM24-Sox2轴在基底膜干性和侵袭性中的重要作用，表明TRIM24是有效基底膜管理的潜在靶点。
Background. Glioblastoma stem cells (GSCs) are a subpopulation of glioblastoma (GBM) cells that are critical for tumor invasion and treatment resistance. However, little is known about the function and mechanism of tripartite motif-containing 24 (TRIM24) in GSCs.Methods. Immunofluorescence, flow cytometry, and western blot analyses were used to evaluate TRIM24 and cluster of differentiation (CD)133 expression profiles in GBM surgical specimens and GSC tumorspheres. Different TRIM24 expression levels in patients' tumors, as measured by both immunohistochemistry and western blot, were related to their corresponding MRI data. Wound healing, Matrigel invasion, and xenograft immunohistochemistry were conducted to determine GBM cell invasion.Results. We identified that TRIM24 was coexpressed with CD133 and Nestin in GBM tissues and tumorsphere cells. Limiting dilution assays and xenotransplantation experiments illustrated that knockdown of TRIM24 expression reduced GSC self-renewal capacity and invasive growth. TRIM24 expression levels were positively associated with the volumes of peritumoral T2 weighted image abnormality. Rescue experiments indicated TRIM24 participation in GBM infiltrative dissemination. Chromatin immunoprecipitation, reporter gene assay, PCR, western blot, and immunohistochemistry demonstrated that TRIM24 activated the expression of the pluripotency transcription factor sex determining region Y-box 2 (Sox2) to regulate GBM stemness and invasion in vitro and in vivo. Finally, the close relationship between TRIM24 and Sox2 was validated by testing samples enrolled in our study and exploring external databases.Conclusions. Our findings uncover essential roles of the TRIM24-Sox2 axis in GBM stemness and invasiveness, suggesting TRIM24 as a potential target for effective GBM management.