Stassen Oscar M J A, van Bodegraven Emma J, Giuliani Fabrizio, Moeton Martina, Kanski Regina, Sluijs Jacqueline A, van Strien Miriam E, Kamphuis Willem, Robe Pierre A J, Hol Elly M
Netherlands Institute for Neuroscience, an Institute of The Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands.
Soft Tissue Engineering and Mechanobiology, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands.
Oncotarget. 2017 Oct 4;8(50):88104-88121. doi: 10.18632/oncotarget.21540. eCollection 2017 Oct 20.
Astrocytomas are the most common malignant brain tumours and are to date incurable. It is unclear how astrocytomas progress into higher malignant grades. The intermediate filament cytoskeleton is emerging as an important regulator of malignancy in several tumours. The majority of the astrocytomas express the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP). Several splice variants have been identified and the main variants expressed in human astrocytoma are the α and δ isoforms. Here we show a significant downregulation of α in grade IV astrocytoma compared to grade II and III, resulting in an increased GFAPδ/ ratio. Mimicking this increase in ratio in astrocytoma cell lines and comparing the subsequent transcriptomic changes with the changes in the patient tumours, we have identified a set of ratio-regulated high-malignant and low-malignant genes. These genes are involved in cell proliferation and protein phosphorylation, and their expression correlated with patient survival. We additionally show that changing the ratio of , by targeting expression, affected expression of high-malignant genes. Our data imply that regulating expression and splicing are novel therapeutic targets that need to be considered as a treatment for astrocytoma.
星形细胞瘤是最常见的恶性脑肿瘤，迄今为止无法治愈。目前尚不清楚星形细胞瘤如何进展为更高的恶性级别。中间丝细胞骨架正在成为几种肿瘤中恶性程度的重要调节因子。大多数星形细胞瘤表达中间丝蛋白胶质纤维酸性蛋白（GFAP）。已鉴定出几种剪接变体，在人类星形细胞瘤中表达的主要变体是α和δ异构体。在这里，我们显示与II级和III级相比，IV级星形细胞瘤中α显著下调，导致GFAPδ/比率增加。在星形细胞瘤细胞系中模拟这种比率增加，并将随后的转录组变化与患者肿瘤中的变化进行比较，我们确定了一组比率调节的高恶性和低恶性基因。这些基因参与细胞增殖和蛋白质磷酸化，它们的表达与患者生存率相关。我们还表明，通过靶向表达改变α/δ比率会影响高恶性基因的表达。我们的数据表明，调节α表达和剪接是需要作为星形细胞瘤治疗方法考虑的新型治疗靶点。
