ISL1 promotes human glioblastoma-derived stem cells self-renewal by activation of SHH/GLI1 function
ISL1 promotes human glioblastoma-derived stem cells self-renewal by activation of SHH/GLI1 function
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ISL1通过激活SHH/GLI1功能促进人胶质母细胞瘤干细胞自我更新
DOI：
10.1089/scd.2021.0344
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发表时间：
2022
影响因子：
4
通讯作者：
Xinlin Chen
中科院分区：
文献类型：
--
作者：
Yingfei Liu;Yan Luan;Kaige Ma;Zhichao Zhang;Yong Liu;Xinlin Chen
胶质母细胞瘤（GBM）是最具侵袭性的原发性异质性原发性脑肿瘤，是起源于中枢神经系统胶质细胞的胶质瘤亚型。胶质母细胞瘤干细胞（GSC）位于层级的顶部，启动和维持肿瘤，并且在很大程度上负责GBM对主要治疗和复发的抗性。LIM同源框转录因子胰岛1（ISL 1）在多种肿瘤中诱导致瘤性;然而，其在GSC中的功能报道较少。我们的目的是从人GBM的手术标本中产生GSC，并研究ISL 1敲低对GSC的影响。我们建立了患者来源的GSC，确定了癌症干细胞标志物表达，并对GSC进行免疫染色以评估细胞活力和凋亡。我们发现，ISL 1基因敲除可降低GSC的存活率和增殖能力，并上调其凋亡;此外，我们通过酶联免疫吸附试验和蛋白质印迹法发现，ISL 1基因敲除可影响音刺猬蛋白（SHH）及其下游调控因子GLI 1的表达，并通过补充重组SHH进一步验证了这些结果。我们的研究结果表明，ISL 1在调节GBM生长中起着关键作用，并且需要ISL 1/SHH/GLI 1通路来维持GBM进展和恶性。通过ISL 1调节GSC生长可能是未来治疗研究的一个感兴趣的机制。
Glioblastoma (GBM), the most aggressive primary heterogeneous primary brain tumor, is a glioma subtype that originates from the glial cells of the central nervous system. Glioblastoma stem cells (GSCs), situated at the top of the hierarchy, initiate and maintain the tumor and are largely accountable for GBM resistance to the mainstay treatment and recurrence. The LIM homeobox transcription factor islet 1 (ISL1) induces tumorigenicity in various tumors; however, its function in GSCs has been less reported. We aimed to generate GSCs from surgical specimens of human GBM and investigate the effect of ISL1 knockdown on GSCs. We established patient-derived GSCs, determined cancer stem cell marker expression, and immunostained GSCs to assess cell viability and apoptosis. We demonstrated that ISL1 deletion decreased the GSC viability and proliferation, and upregulated apoptosis.Moreover, we performed enzyme-linked immunosorbent assay and western blotting and found that ISL1 knockdown affected the expression of sonic hedgehog (SHH) and its downstream regulator GLI1, and further validated these results by supplementing the cells with recombinant SHH. Our results suggested that ISL1 played a critical role in regulating GBM growth and that an ISL1/SHH/GLI1 pathway was required for the maintenance of GBM progression and malignancy. The regulation of GSC growth through ISL1 might be a mechanism of interest for future therapeutic studies.