PDF(Pubmed)
Abstract：
Glioblastoma (GBM) is a highly angiogenic malignancy of the central nervous system that resists standard antiangiogenic therapy, in part because of an alternative process to angiogenesis termed vasculogenic mimicry. Intricately linked to GBM, dysregulation of the Hippo signaling pathway leads to overexpression of YAP/TEAD and several downstream effectors involved in therapy resistance. Little is known about whether vasculogenic mimicry and the Hippo pathway intersect in the GBM chemoresistance phenotype. This study seeks to investigate the expression patterns of Hippo pathway regulators within clinically annotated GBM samples, examining their involvement in vitro regarding vasculogenic mimicry. In addition, it aims to assess the potential for pharmacological targeting of this pathway. In-silico analysis of the Hippo signaling members YAP1 , TEAD1 , AXL , NF2 , CTGF , and CYR61 transcript levels in low-grade GBM and GBM tumor tissues was done by Gene Expression Profiling Interactive Analysis. Gene expression was analyzed by real-time quantitative PCR from human U87, U118, U138, and U251 brain cancer cell lines and in clinically annotated brain tumor cDNA arrays. Transient gene silencing was performed with specific small interfering RNA. Vasculogenic mimicry was assessed using a Cultrex matrix, and three-dimensional capillary-like structures were analyzed with Wimasis. CYR61 and CTGF transcript levels were elevated in GBM tissues and were further induced when in-vitro vasculogenic mimicry was assessed. Silencing of CYR61 and CTGF , or treatment with a small-molecule TEAD inhibitor LM98 derived from flufenamic acid, inhibited vasculogenic mimicry. Silencing of SNAI1 and FOXC2 also altered vasculogenic mimicry and reduced CYR61 / CTGF levels. Pharmacological targeting of the Hippo pathway inhibits in-vitro vasculogenic mimicry. Unraveling the connections between the Hippo pathway and vasculogenic mimicry may pave the way for innovative therapeutic strategies.
摘要：
胶质母细胞瘤（GBM）是中枢神经系统的高度血管生成恶性肿瘤，抵抗标准的抗血管生成治疗，部分原因是血管生成拟态血管生成的替代过程。与GBM紧密相关，Hippo信号通路的失调导致YAP/TEAD和几种参与治疗抗性的下游效应物的过表达。关于血管生成拟态和Hippo途径在GBM化学抗性表型中是否相交知之甚少。本研究旨在研究临床注释GBM样品中Hippo通路调节因子的表达模式，检查他们在体外关于血管生成拟态的参与。此外,它旨在评估该途径的药理靶向潜力。Hippo信号转导成员YAP1、TEAD1、AXL、NF2,CTGF,低级别GBM和GBM肿瘤组织中的CYR61转录物水平通过基因表达谱交互式分析进行。通过实时定量PCR分析来自人U87，U118，U138和U251脑癌细胞系以及临床注释的脑肿瘤cDNA阵列的基因表达。用特异性小干扰RNA进行瞬时基因沉默。使用Cultrex基质评估血管生成拟态，并用Wimasis分析了三维毛细管样结构。CYR61和CTGF转录物水平在GBM组织中升高，并在评估体外血管生成拟态时进一步诱导。沉默CYR61和CTGF，或用来自氟芬那酸的小分子TEAD抑制剂LM98治疗，抑制血管生成拟态。SNAI1和FOXC2的沉默也改变了血管生成拟态并降低了CYR61/CTGF水平。Hippo途径的药理学靶向抑制体外血管生成拟态。解开Hippo途径与血管生成拟态之间的联系可能为创新的治疗策略铺平道路。
