1School of Medicine, Chang Gung University, Taoyuan.
Departments of2Neurosurgery.
J Neurosurg. 2019 Jan 11;132(1):168-179. doi: 10.3171/2018.8.JNS181217. Print 2020 Jan 1.
Despite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment.
IGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models.
We demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice.
Our findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.
尽管进行了强化治疗，胶质母细胞瘤（IV 级胶质瘤[GBM]）患者的 5 年生存率仍仅有 5.5%。本研究旨在通过鉴定治疗靶点 IGFBP3 来改善目前的治疗方法。
分析 135 例新诊断为胶质瘤患者的 IGFBP3 RNA 表达与临床病理因素的相关性。采用免疫组织化学分析检测 IGFBP3 蛋白在胶质瘤标本中的表达。通过 IGFBP3 敲低胶质瘤细胞来检测 IGFBP3 耗竭对细胞增殖的影响。采用 IGFBP3 siRNA 颅内输注来评估 IGFBP3 耗竭在小鼠颅内异种移植模型中的作用。
我们发现 IGFBP3 在 GBM 中的表达高于肿瘤边缘和 II 级胶质瘤。IGFBP3 的表达不仅与肿瘤分级呈正相关，还与肿瘤组织学和 IDH1/2 突变状态相关。此外，IGFBP3 表达较高与胶质瘤患者和 GBM 神经前体细胞亚组患者的总生存期较短相关。体外细胞培养研究表明，IGFBP3 敲低抑制了胶质瘤细胞的增殖，并诱导细胞周期 G2/M 期阻滞和细胞凋亡。IGFBP3 敲低细胞中还观察到 DNA 双链断裂和 γH2AX 的积累。IGFBP3 敲低延迟了小鼠皮下异种移植模型中的肿瘤生长。此外，IGFBP3 siRNA 的对流增强递送抑制了小鼠脑内肿瘤生长并延长了荷瘤小鼠的生存时间。
我们的研究结果表明 IGFBP3 可预测胶质瘤患者的不良预后，是一种潜在的治疗靶点，通过诱导细胞凋亡和在胶质瘤细胞中积累 DNA 损伤来抑制肿瘤生长。
