Division of Neuroanatomy, Medical University of Innsbruck, Innsbruck, Austria.
Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Division of Virology, Medical University of Innsbruck, Innsbruck, Austria.
Neuro Oncol. 2018 Jul 5;20(8):1044-1054. doi: 10.1093/neuonc/noy028.
Sprouty2 (SPRY2), a feedback regulator of receptor tyrosine kinase (RTK) signaling, has been shown to be associated with drug resistance and cell proliferation in glioblastoma (GBM), but the underlying mechanisms are still poorly defined.
SPRY2 expression and survival patterns of patients with gliomas were analyzed using publicly available databases. Effects of RNA interference targeting SPRY2 on cellular proliferation in established GBM or patient-derived GBM stemlike cells were examined. Loss- or gain-of-function of SPRY2 to regulate the tumorigenic capacity was assessed in both intracranial and subcutaneous xenografts.
SPRY2 was found to be upregulated in GBM, which correlated with reduced survival in GBM patients. SPRY2 knockdown significantly impaired proliferation of GBM cells but not of normal astrocytes. Silencing of SPRY2 increased epidermal growth factor-induced extracellular signal-regulated kinase (ERK) and Akt activation causing premature onset of DNA replication, increased DNA damage, and impaired proliferation, suggesting that SPRY2 suppresses DNA replication stress. Abrogating SPRY2 function strongly inhibited intracranial tumor growth and led to significantly prolonged survival of U87 xenograft-bearing mice. In contrast, SPRY2 overexpression promoted tumor propagation of low-tumorigenic U251 cells.
The present study highlights an antitumoral effect of SPRY2 inhibition that is based on excessive activation of ERK signaling and DNA damage response, resulting in reduced cell proliferation and increased cytotoxicity, proposing SPRY2 as a promising pharmacological target in GBM patients.
Sprouty2（SPRY2）作为受体酪氨酸激酶（RTK）信号的反馈调节剂，已被证明与胶质母细胞瘤（GBM）的耐药性和细胞增殖有关，但潜在的机制仍不清楚。
使用公共可用数据库分析了Sprouty2 在胶质瘤患者中的表达和生存模式。通过 RNA 干扰靶向 Sprouty2 检测其对已建立的 GBM 或患者来源的 GBM 干细胞样细胞中细胞增殖的影响。通过 Sprouty2 的缺失或功能获得来评估其对颅内和皮下异种移植物中致瘤能力的调节作用。
发现 Sprouty2 在 GBM 中上调，这与 GBM 患者的生存时间缩短有关。Sprouty2 敲低显著抑制了 GBM 细胞的增殖，但对正常星形胶质细胞没有影响。Sprouty2 的沉默增加了表皮生长因子诱导的细胞外信号调节激酶（ERK）和 Akt 的激活，导致 DNA 复制的提前启动、增加的 DNA 损伤和增殖受损，表明 Sprouty2 抑制了 DNA 复制应激。破坏 Sprouty2 的功能强烈抑制了颅内肿瘤的生长，并显著延长了 U87 异种移植小鼠的存活时间。相比之下，Sprouty2 的过表达促进了低致瘤性 U251 细胞的肿瘤传播。
本研究强调了 Sprouty2 抑制的抗肿瘤作用，其基础是 ERK 信号和 DNA 损伤反应的过度激活，导致细胞增殖减少和细胞毒性增加，为 GBM 患者提出了 Sprouty2 作为有前途的药物靶点。
