van Vuurden Dannis G, Aronica Eleonora, Hulleman Esther, Wedekind Laurine E, Biesmans Dennis, Malekzadeh Arjan, Bugiani Marianna, Geerts Dirk, Noske David P, Vandertop W Peter, Kaspers Gertjan J L, Cloos Jacqueline, Würdinger Thomas, van der Stoop Petra P M
Neuro Oncol. 2014 Jul;16(7):946-59. doi: 10.1093/neuonc/not308.
Glial brain tumors cause considerable mortality and morbidity in children and adults. Innovative targets for therapy are needed to improve survival and reduce long-term sequelae. The aim of this study was to find a candidate tumor-promoting protein, abundantly expressed in tumor cells but not in normal brain tissues, as a potential target for therapy.
In silico proteomics and genomics, immunohistochemistry, and immunofluorescence microscopy validation were performed. RNA interference was used to ascertain the functional role of the overexpressed candidate target protein.
In silico proteomics and genomics revealed pre-B-cell leukemia homeobox (PBX) interacting protein 1 (PBXIP1) overexpression in adult and childhood high-grade glioma and ependymoma compared with normal brain. PBXIP1 is a PBX-family interacting microtubule-binding protein with a putative role in migration and proliferation of cancer cells. Immunohistochemical studies in glial tumors validated PBXIP1 expression in astrocytoma and ependymoma but not in oligodendroglioma. RNAi-mediated PBXIP1-knockdown in glioblastoma cell lines strongly reduced proliferation and migration and induced morphological changes, indicating that PBXIP1 knockdown decreases glioma cell viability and motility through rearrangements of the actin cytoskeleton. Furthermore, expression of PBXIP1 was observed in radial glia and astrocytic progenitor cells in human fetal tissues, suggesting that PBXIP1 is an astroglial progenitor cell marker during human embryonic development.
PBXIP1 is a novel protein overexpressed in astrocytoma and ependymoma, involved in tumor cell proliferation and migration, that warrants further exploration as a novel therapeutic target in these tumors.
胶质脑肿瘤在儿童和成人中导致相当高的死亡率和发病率。需要创新的治疗靶点来提高生存率并减少长期后遗症。本研究的目的是找到一种在肿瘤细胞中大量表达但在正常脑组织中不表达的候选促肿瘤蛋白，作为潜在的治疗靶点。
进行了计算机蛋白质组学和基因组学、免疫组织化学及免疫荧光显微镜验证。使用RNA干扰来确定过表达的候选靶蛋白的功能作用。
计算机蛋白质组学和基因组学显示，与正常脑相比，前B细胞白血病同源盒（PBX）相互作用蛋白1（PBXIP1）在成人和儿童高级别胶质瘤及室管膜瘤中过表达。PBXIP1是一种PBX家族相互作用的微管结合蛋白，在癌细胞的迁移和增殖中可能起作用。胶质肿瘤的免疫组织化学研究证实PBXIP1在星形细胞瘤和室管膜瘤中表达，但在少突胶质细胞瘤中不表达。RNAi介导的胶质母细胞瘤细胞系中PBXIP1敲低显著降低了增殖和迁移并诱导了形态学变化，表明PBXIP1敲低通过肌动蛋白细胞骨架重排降低了胶质瘤细胞的活力和运动性。此外，在人胎儿组织的放射状胶质细胞和星形胶质细胞祖细胞中观察到了PBXIP1的表达，提示PBXIP1是人类胚胎发育过程中的星形胶质细胞祖细胞标志物。
PBXIP1是一种在星形细胞瘤和室管膜瘤中过表达的新型蛋白，参与肿瘤细胞增殖和迁移，作为这些肿瘤的新型治疗靶点值得进一步探索。
