ΔNp73/ETS2 复合物驱动胶质母细胞瘤发病机制-通过雷巴替尼靶向下游介质可延长胶质母细胞瘤临床前模型的存活时间。
ΔNp73/ETS2 complex drives glioblastoma pathogenesis- targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma.
机构信息
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
Cancer Center and Regenerative Medicine, Massachusetts General Hospital, Boston.
出版信息
Neuro Oncol. 2020 Mar 5;22(3):345-356. doi: 10.1093/neuonc/noz190.
BACKGROUND
Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isoform of TP73, and to evaluate targeting of its downstream mediators, the angiopoietin 1 (ANGPT1)/tunica interna endothelial cell kinase 2 (Tie2) axis, by using a highly potent, orally available small-molecule inhibitor (rebastinib) in GBM.
METHODS
ΔNp73 expression was assessed in glioma sphere cultures, xenograft glioblastoma tumors, and glioblastoma patients by western blot, quantitative reverse transcription PCR, and immunohistochemistry. Immunoprecipitation, chromatin immunoprecipitation (ChiP) and sequential ChIP were performed to determine the interaction between ΔNp73 and E26 transformation-specific (ETS) proto-oncogene 2 (ETS2) proteins. The oncogenic consequences of ΔNp73 expression in glioblastomas were examined by in vitro and in vivo experiments, including orthotopic zebrafish and mouse intracranial-injection models. Effects of rebastinib on growth of established tumors and survival were examined in an intracranial-injection mouse model.
RESULTS
ΔNp73 upregulates both ANGPT1 and Tie2 transcriptionally through ETS conserved binding sites on the promoters by interacting with ETS2. Elevated expression of ΔNp73 promotes tumor progression by mediating angiogenesis and survival. Therapeutic targeting of downstream ΔNp73 signaling pathways by rebastinib inhibits growth of established tumors and extends survival in preclinical models of glioblastoma.
CONCLUSION
Aberrant expression of ΔNp73 in GBM promotes tumor progression through autocrine and paracrine signaling dependent on Tie2 activation by ANGPT1. Disruption of this signaling by rebastinib improves tumor response to treatment in glioblastoma.
背景
胶质母细胞瘤（GBM）仍然是治疗效果最差的癌症之一。了解这种致命疾病的基本生物学特性并研究治疗 GBM 的新型药理学靶点至关重要。本研究旨在确定高表达 ΔNp73（TP73 的 N 端截断异构体）的生物学后果，并通过使用高活性、口服有效的小分子抑制剂（rebastinib）评估其下游介质血管生成素 1（ANGPT1）/血管内皮细胞激酶 2（Tie2）轴的靶向作用在 GBM 中。
方法
通过 Western blot、定量逆转录 PCR 和免疫组织化学评估胶质瘤球体培养物、异种移植 GBM 肿瘤和 GBM 患者中的 ΔNp73 表达。进行免疫沉淀、染色质免疫沉淀（ChiP）和连续 ChiP 以确定 ΔNp73 与 E26 转化特异性（ETS）原癌基因 2（ETS2）蛋白之间的相互作用。通过体外和体内实验（包括正交斑马鱼和小鼠颅内注射模型）研究 ΔNp73 在胶质母细胞瘤中的致癌后果。在颅内注射小鼠模型中检查 rebastinib 对已建立肿瘤生长和存活的影响。
结果
ΔNp73 通过与 ETS2 相互作用，在启动子上的 ETS 保守结合位点上转录上调 ANGPT1 和 Tie2。ΔNp73 的高表达通过介导血管生成和存活促进肿瘤进展。通过 rebastinib 对下游 ΔNp73 信号通路的治疗靶向抑制了临床前 GBM 模型中已建立肿瘤的生长并延长了存活。
结论
GBM 中 ΔNp73 的异常表达通过依赖于 ANGPT1 激活 Tie2 的自分泌和旁分泌信号促进肿瘤进展。rebastinib 破坏这种信号转导可改善 GBM 对治疗的肿瘤反应。
Zotero 插件