Jungwirth Gerhard, Yu Tao, Moustafa Mahmoud, Rapp Carmen, Warta Rolf, Jungk Christine, Sahm Felix, Dettling Steffen, Zweckberger Klaus, Lamszus Katrin, Senft Christian, Loehr Mario, Keßler Almuth F, Ketter Ralf, Westphal Manfred, Debus Juergen, von Deimling Andreas, Simon Matthias, Unterberg Andreas, Abdollahi Amir, Herold-Mende Christel
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, INF 400, D-69120 Heidelberg, Germany.
Department of Radiation Oncology, University of Heidelberg, INF 400, D-69120 Heidelberg, Germany.
Cancers (Basel). 2019 Apr 15;11(4):545. doi: 10.3390/cancers11040545.
Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas ( = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample ( = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I = 61, WHO°II = 88, and WHO°III = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.
驱动蛋白在包括细胞内囊泡运输和有丝分裂在内的许多生理功能中发挥着重要作用。驱动蛋白在不同癌症中的新作用促使我们研究其在脑膜瘤中的表达及功能作用。因此，我们重新分析了之前关于良性、非典型和间变性脑膜瘤（n = 62）的微阵列数据集，发现了5种驱动蛋白（KIFC1、KIF4A、KIF11、KIF14和KIF20A）的差异表达。在一个扩大的研究样本（n = 208）中进一步验证发现，这些基因在世界卫生组织（WHO）I级至III级脑膜瘤（WHO I级n = 61，WHO II级n = 88，WHO III级n = 59）中显著上调，在相同WHO分级的临床侵袭性更强的肿瘤中最为明显。免疫组织化学染色证实脑膜瘤组织中存在与WHO分级相关的蛋白表达上调。此外，KIFC1、KIF11、KIF14和KIF20A的高mRNA表达水平与无进展生存期缩短相关。在功能水平上，在Ben-Men-1细胞和新建立的间变性脑膜瘤细胞系NCH93中敲低驱动蛋白，通过siRNA介导下调KIF11，两个细胞系中的肿瘤细胞增殖分别显著受到抑制，抑制率高达95%和71%。综上所述，在本研究中，我们能够确定几种驱动蛋白家族成员的预后和功能作用，其中KIF11作为一种新的预后标志物和治疗靶点具有最有前景的特性，这可能为侵袭性脑膜瘤提供新的治疗选择。
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