Krassnig Stefanie, Wohlrab Christina, Golob-Schwarzl Nicole, Raicht Andrea, Schatz Christoph, Birkl-Toeglhofer Anna Maria, Skofler Christina, Gantenbein Nadine, Leoni Marlene, Asslaber Martin, Leber Stefan L, Mahdy-Ali Kariem, von Campe Gord, Mayer Marlene, Borenich Andrea, Weis Serge, Benesch Martin, Haybaeck Johannes
Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria.
Department of Dermatology and Venereology, Medical University Graz, Auenbruggerplatz 8, 8036 Graz, Austria.
Cancers (Basel). 2021 Mar 23;13(6):1482. doi: 10.3390/cancers13061482.
Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients' overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I-IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients' survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.
胶质母细胞瘤（GBM）是一种极具毁灭性的脑肿瘤，目前的治疗方法仅能略微提高患者的总生存期（OS）。PI3K/AKT/mTOR信号通路通过调节细胞生长和增殖参与胶质瘤的发生。由于它是由真核起始因子（eIFs）控制的蛋白质合成限速翻译起始步骤的上游调节因子，我们旨在对17种eIFs进行深入的基础表征，以确定胶质瘤潜在的新型治疗靶点。因此，我们回顾性分析了人星形细胞瘤样本（WHO I-IV级）中mTOR相关蛋白和eIFs的表达，并使用免疫印迹分析和免疫组织化学将其与非肿瘤性皮质对照脑组织（CCBT）进行比较。我们使用qRT-PCR检测mRNA表达，并另外进行了计算机分析以观察eIFs对患者生存的影响。与CCBT相比，高级别胶质瘤中eIF3B、eIF3I、eIF4A1、eIF4H、eIF5和eIF6的蛋白质和mRNA表达显著增加，低级别胶质瘤中部分增加。然而，短生存期仅与低级别胶质瘤中高eIF3I基因表达相关，而与GBM无关。在GBM中，高eIF4H基因表达与患者较短生存期显著相关。总之，我们确定eIF3I和eIF4H是未来胶质瘤患者治疗最有前景的靶点。
