Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China; Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
Pathol Res Pract. 2019 Nov;215(11):152617. doi: 10.1016/j.prp.2019.152617. Epub 2019 Aug 23.
Recent studies have demonstrated that aberrant expression or activation of kinases results in oncogenesis of a wide range of cancers including GBM. Inhibition of kinases expression induces a reduction of therapy resistance. In this study, we investigate the underlying mechanism by which glioblastoma (GBM) cells acquire resistance to Temozolomide (TMZ) through Aurora kinase B (AURKB) thus to identify novel therapeutic targets and prognostic biomarkers for GBM.
AURKB was identified as a key candidate kinase-encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of AURKB in oncogenesis and chemoresistance were investigated by lentivirus-dependent silencing of AURKB combined with qRT-PCR, western blot and in vivo intra-cranial xenograft mice models. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. Lastly, Chou-Talalay method was used to confirm the synergistic effect of TMZ combined with AURKB inhibitor.
AURKB was among the most significantly up-regulated kinase-coding genes in TMZ resistant GBM cells according to database GSE68029, moreover, an increased expression of AURKB was closely associated with poor prognosis in glioma and GBM patients. AURKB knock-down resensitized U87 resistant cells to TMZ both in vitro and in vivo. Additionally, the combination of TMZ and Hesperadin, a specific AURKB inhibitor, significantly suppressed the proliferation of TMZ resistant GBM cells thus dramatically prolonged the survival of xenograft mice viaa synergistic effect with TMZ.
Elevated AURKB expression was strongly correlated to TMZ resistant acquisition and poor prognosis, furthermore, targeting AURKB would be a potential therapeutic target for GBM patients.
最近的研究表明，激酶的异常表达或激活导致广泛的癌症发生，包括 GBM。抑制激酶的表达会诱导治疗耐药性的降低。在这项研究中，我们通过 Aurora 激酶 B（AURKB）研究胶质母细胞瘤（GBM）细胞获得替莫唑胺（TMZ）耐药的潜在机制，从而确定新的 GBM 治疗靶点和预后生物标志物。
通过激酶组全生物信息学分析，确定 AURKB 是化学耐药性调节中的关键候选激酶编码基因。随后，通过依赖慢病毒的 AURKB 沉默结合 qRT-PCR、western blot 和体内颅内异种移植小鼠模型研究 AURKB 在肿瘤发生和化学耐药性中的潜在生物学功能。此外，进行免疫组织化学（IHC）检测以探索 AURKB 在 glioma 患者中的临床意义。最后，采用 Chou-Talalay 方法确认 TMZ 与 AURKB 抑制剂联合的协同作用。
根据数据库 GSE68029，AURKB 是 TMZ 耐药 GBM 细胞中上调最显著的激酶编码基因之一，此外，AURKB 的表达增加与 glioma 和 GBM 患者的预后不良密切相关。AURKB 敲低使 U87 耐药细胞在体外和体内均对 TMZ 重新敏感。此外，TMZ 与 Hesperadin（一种特异性 AURKB 抑制剂）的联合使用通过与 TMZ 的协同作用，显著抑制 TMZ 耐药 GBM 细胞的增殖，从而显著延长异种移植小鼠的存活时间。
AURKB 表达升高与 TMZ 耐药性获得和预后不良密切相关，此外，靶向 AURKB 可能是 GBM 患者的潜在治疗靶点。
