Lötsch Daniela, Steiner Elisabeth, Holzmann Klaus, Spiegl-Kreinecker Sabine, Pirker Christine, Hlavaty Juraj, Petznek Helga, Hegedus Balazs, Garay Tamas, Mohr Thomas, Sommergruber Wolfgang, Grusch Michael, Berger Walter
Institute of Cancer Research, Department of Medicine I.
Oncotarget. 2013 Nov;4(11):1904-18. doi: 10.18632/oncotarget.1264.
Despite their ubiquitous expression and high conservation during evolution, precise cellular functions of vault ribonucleoparticles, mainly built of multiple major vault protein (MVP) copies, are still enigmatic. With regard to cancer, vaults were shown to be upregulated during drug resistance development as well as malignant transformation and progression. Such in a previous study we demonstrated that human astrocytic brain tumours including glioblastoma are generally high in vault levels while MVP expression in normal brain is comparably low. However a direct contribution to the malignant phenotype in general and that of glioblastoma in particular has not been established so far. Thus we address the questions whether MVP itself has a pro-tumorigenic function in glioblastoma. Based on a large tissue collection, we re-confirm strong MVP expression in gliomas as compared to healthy brain. Further, the impact of MVP on human glioblastoma aggressiveness was analysed by using gene transfection, siRNA knock-down and dominant-negative genetic approaches. Our results demonstrate that MVP/vaults significantly support migratory and invasive competence as well as starvation resistance of glioma cells in vitro and in vivo. The enhanced aggressiveness was based on MVP-mediated stabilization of the epidermal growth factor receptor (EGFR)/phosphatidyl-inositol-3-kinase (PI3K) signalling axis. Consequently, MVP overexpression resulted in enhanced growth and brain invasion in human glioblastoma xenograft models. Our study demonstrates, for the first time, that vaults have a tumour-promoting potential by stabilizing EGFR/PI3K-mediated migration and survival pathways in human glioblastoma.
尽管穹窿核糖核蛋白体在进化过程中普遍表达且高度保守，但其精确的细胞功能仍然成谜，该蛋白体主要由多个主要穹窿蛋白（MVP）拷贝组成。关于癌症，研究表明在耐药性发展以及恶性转化和进展过程中，穹窿蛋白会上调。此前我们的一项研究表明，包括胶质母细胞瘤在内的人类星形细胞脑肿瘤中穹窿蛋白水平普遍较高，而正常脑组织中MVP的表达相对较低。然而，目前尚未确定其对一般恶性表型，特别是胶质母细胞瘤恶性表型的直接作用。因此，我们探讨了MVP本身在胶质母细胞瘤中是否具有促肿瘤功能这一问题。基于大量组织样本，我们再次证实与健康脑组织相比，胶质瘤中MVP表达强烈。此外，我们通过基因转染、siRNA敲低和显性负性基因方法分析了MVP对人类胶质母细胞瘤侵袭性的影响。我们的结果表明，MVP/穹窿蛋白体在体外和体内均能显著增强胶质瘤细胞的迁移和侵袭能力以及抗饥饿能力。侵袭性增强是基于MVP介导的表皮生长因子受体（EGFR）/磷脂酰肌醇-3-激酶（PI3K）信号轴的稳定。因此，在人胶质母细胞瘤异种移植模型中，MVP过表达导致肿瘤生长加快和脑侵袭增强。我们的研究首次表明，穹窿蛋白体通过稳定人胶质母细胞瘤中EGFR/PI3K介导的迁移和生存途径具有促进肿瘤的潜力。
