Expression of dynein, cytoplasmic 2, heavy chain 1 (DHC2) associated with glioblastoma cell resistance to temozolomide.
Expression of dynein, cytoplasmic 2, heavy chain 1 (DHC2) associated with glioblastoma cell resistance to temozolomide.
复制标题
动力蛋白、细胞质 2、重链 1 (DHC2) 的表达与胶质母细胞瘤细胞对替莫唑胺的耐药性相关
DOI：
10.1038/srep28948
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发表时间：
2016-07-04
影响因子：
4.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Wang H;Feng W;Lu Y;Li H;Xiang W;Chen Z;He M;Zhao L;Sun X;Lei B;Qi S;Liu Y
替莫唑胺（TMZ）是治疗多形性胶质母细胞瘤（GMB）的主要化疗药物，然而，耐药性往往导致肿瘤复发和不良结局。用TMZ处理GMB细胞系长达两周，然后进行蛋白质组学分析以鉴定与TMZ抗性相关的潜在分子病理学。蛋白质组学数据显示，TMZ改变了与细胞骨架结构和功能相关的蛋白质的表达，如DHC 2和KIF 2B。使用qRT-PCR和免疫荧光来验证这些细胞中DHC 2和KIF 2B的表达。免疫组织化学用于验证这两种蛋白在裸鼠模型的异种移植物和体内GBM组织样品中的表达。使用siRNA敲低它们的表达以确认它们在GBM细胞对TMZ敏感性的调节中的作用。DHC 2表达下调可增强U87细胞对TMZ治疗的敏感性，体外研究表明，DHC 2在GBM组织中的表达与TMZ化疗后的肿瘤复发相关。这些结果表明，细胞骨架相关蛋白DHC 2降低GBM细胞对TMZ处理的敏感性。进一步的研究应评估DHC 2作为TMZ联合治疗GBM的新靶点。
Temozolomide (TMZ) is the main chemotherapeutic drug utilized for the treatment of glioblastoma multiforme (GMB), however, drug resistance often leads to tumor recurrence and poor outcomes. GMB cell lines were treated with TMZ for up to two weeks and then subjected to proteomics analysis to identify the underlying molecular pathology that is associated with TMZ resistance. Proteomics data showed that TMZ altered expression of proteins that related to cytoskeleton structure and function, such as DHC2 and KIF2B. qRT-PCR and immunofluorescence were used to verify expression of DHC2 and KIF2B in these cells. Immunohistochemistry was used to verify expression of these two proteins in xenografts of a nude mouse model andex vivoGBM tissue samples. Their expression was knocked down using siRNA to confirm their role in the regulation of GBM cell sensitivity to TMZ. Knockdown of DHC2 expression enhanced sensitivity of U87 cells to TMZ treatment.Ex vivodata showed that DHC2 expression in GBM tissue samples was associated with tumor recurrence after TMZ chemotherapy. These results indicated cytoskeleton related protein DHC2 reduced sensitivity of GBM cells to TMZ treatment. Further studies should assess DHC2 as a novel target in GBM for TMZ combination treatment.