Roy Marie-Eve, Elimam Rahil, Zgheib Alain, Annabi Borhane
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montreal, Quebec, Canada.
J Cell Mol Med. 2024 Dec;28(24):e70304. doi: 10.1111/jcmm.70304.
The Hippo pathway plays a tumorigenic role in highly angiogenic glioblastoma (GBM), whereas little is known about clinically relevant Hippo pathway inhibitors' ability to target adaptive mechanisms involved in GBM chemoresistance. Their molecular impact was investigated here in vitro against an alternative process to tumour angiogenesis termed vasculogenic mimicry (VM) in GBM-derived cell models. In silico analysis of the downstream Hippo signalling members YAP1, TAZ and TEAD1 transcript levels in low-grade glioblastoma (LGG) and GBM tumour tissues was performed using GEPIA. TAZ transcript levels did not differ between the healthy and tumour tissues data analysed. In contrast, YAP1 transcript levels were elevated in GBM tissues, whereas TEAD1 levels were high in both LGG and GBM. All three Hippo pathway inhibitors tested, GNE7883, VT107 and IAG933 effectively inhibited U87 and U251 cell migration and in vitro VM as assessed on Cultrex matrix. YAP1 gene and protein expression were induced upon VM, and its translocation to the nucleus was inhibited by the Hippo pathway inhibitors tested. SiRNA-mediated transient silencing of YAP1 repressed cell migration, VM formation and CTGF and Cyr61 transcription. In conclusion, targeting of VM using Hippo pathway inhibitors could help circumvent GBM chemoresistance and effectively complement other brain cancer treatments.
河马通路在高度血管生成性胶质母细胞瘤（GBM）中发挥致瘤作用，而对于临床上相关的河马通路抑制剂针对GBM化学抗性中涉及的适应性机制的靶向能力知之甚少。在此，我们在体外针对GBM衍生细胞模型中一种称为血管生成拟态（VM）的肿瘤血管生成替代过程，研究了它们的分子影响。使用GEPIA对低级别胶质瘤（LGG）和GBM肿瘤组织中河马信号通路下游成员YAP1、TAZ和TEAD1的转录水平进行了计算机分析。在分析的健康组织和肿瘤组织数据之间，TAZ转录水平没有差异。相比之下，YAP1转录水平在GBM组织中升高，而TEAD1水平在LGG和GBM中均较高。所测试的三种河马通路抑制剂GNE7883、VT107和IAG933均有效抑制了U87和U251细胞迁移以及在Cultrex基质上评估的体外VM。VM诱导后YAP1基因和蛋白表达增加，而所测试的河马通路抑制剂抑制了其向细胞核的转位。小干扰RNA介导的YAP1瞬时沉默抑制了细胞迁移、VM形成以及CTGF和Cyr61转录。总之，使用河马通路抑制剂靶向VM可能有助于规避GBM化学抗性，并有效补充其他脑癌治疗方法。
