Moriconi Chiara, Civita Prospero, Neto Catia, Pilkington Geoffrey J, Gumbleton Mark
School of Pharmacy and Pharmaceutical Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.
Department of Pathology and Cell Biology, Columbia University, New York Presbyterian Hospital, New York, NY, United States.
Front Oncol. 2021 Aug 20;11:701933. doi: 10.3389/fonc.2021.701933. eCollection 2021.
Glioblastoma (GB) remains an aggressive malignancy with an extremely poor prognosis. Discovering new candidate drug targets for GB remains an unmet medical need. Caveolin-1 (Cav-1) has been shown to act variously as both a tumour suppressor and tumour promoter in many cancers. The implications of Cav-1 expression in GB remains poorly understood. Using clinical and genomic databases we examined the relationship between tumour Cav-1 gene expression (including its spatial distribution) and clinical pathological parameters of the GB tumour and survival probability in a TCGA cohort (n=155) and CGGA cohort (n=220) of GB patients. High expression of Cav-1 represented a significant independent predictor of shortened survival (HR = 2.985, 5.1 14.9 months) with a greater statistically significant impact in female patients and in the Proneural and Mesenchymal GB subtypes. High Cav-1 expression correlated with other factors associated with poor prognosis: IDH w/t status, high histological tumour grade and low KPS score. A total of 4879 differentially expressed genes (DEGs) in the GB tumour were found to correlate with Cav-1 expression (either positively or negatively). Pathway enrichment analysis highlighted an over-representation of these DEGs to certain biological pathways. Focusing on those that lie within a framework of epithelial to mesenchymal transition and tumour cell migration and invasion we identified 27 of these DEGs. We then examined the prognostic value of Cav-1 when used in combination with any of these 27 genes and identified a subset of combinations (with Cav-1) indicative of co-operative synergistic mechanisms of action. Overall, the work has confirmed Cav-1 can serve as an independent prognostic marker in GB, but also augment prognosis when used in combination with a panel of biomarkers or clinicopathologic parameters. Moreover, Cav-1 appears to be linked to many signalling entities within the GB tumour and as such this work begins to substantiate Cav-1 or its associated signalling partners as candidate target for GB new drug discovery.
胶质母细胞瘤（GB）仍然是一种侵袭性恶性肿瘤，预后极差。发现GB的新候选药物靶点仍然是一项未满足的医学需求。在许多癌症中，小窝蛋白-1（Cav-1）已被证明既可以作为肿瘤抑制因子，也可以作为肿瘤促进因子发挥多种作用。Cav-1在GB中的表达意义仍知之甚少。我们使用临床和基因组数据库，在一个由155例GB患者组成的TCGA队列和一个由220例GB患者组成的CGGA队列中，研究了肿瘤Cav-1基因表达（包括其空间分布）与GB肿瘤的临床病理参数及生存概率之间的关系。Cav-1的高表达是生存缩短的一个显著独立预测因子（HR = 2.985，5.1至14.9个月），对女性患者以及神经前体细胞型和间充质细胞型GB亚型具有更大的统计学显著影响。Cav-1的高表达与其他预后不良因素相关：异柠檬酸脱氢酶（IDH）野生型/突变型状态、高组织学肿瘤分级和低KPS评分。在GB肿瘤中总共发现4879个差异表达基因（DEG）与Cav-1表达（正相关或负相关）相关。通路富集分析突出显示这些DEG在某些生物通路中过度富集。聚焦于那些处于上皮-间质转化以及肿瘤细胞迁移和侵袭框架内的通路，我们鉴定出其中27个DEG。然后，我们研究了Cav-1与这27个基因中的任何一个联合使用时的预后价值，并鉴定出一组（与Cav-1联合）表明协同作用机制的组合。总体而言，这项研究证实Cav-1可作为GB的独立预后标志物，但与一组生物标志物或临床病理参数联合使用时也可改善预后。此外，Cav-1似乎与GB肿瘤内的许多信号实体相关，因此这项研究开始证实Cav-1或其相关信号伙伴作为GB新药发现的候选靶点。
