Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, 1678, Nicosia, Cyprus.
College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.
Mol Cell Biochem. 2020 Aug;471(1-2):143-153. doi: 10.1007/s11010-020-03774-y. Epub 2020 Jun 6.
Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor and it is associated with poor survival. Integrin-linked kinase (ILK) is a serine/threonine protein pseudo-kinase that binds to the cytoplasmic domains of β1 and β3 integrins and has been previously shown to promote invasion and metastasis in many cancer types, including GBM. However, little is known regarding the exact molecular mechanism implicating ILK in GBM aggressiveness. In this study, we used two brain cell lines, the non-invasive neuroglioma H4 cells, and the highly invasive glioblastoma A172 cells, which express ILK in much higher levels than H4. We studied the effect of ILK silencing on the metastatic behavior of glioblastoma cells in vitro and elucidate the underlying molecular mechanism. We showed that siRNA-mediated silencing of ILK inhibits cell migration and invasion of the highly invasive A172 cells while it does not affect the migratory and invasive capacity of H4 cells. These data were also supported by respective changes in the expression of Rho-associated kinase 1 (ROCK1), fascin actin-bundling protein 1 (FSCN1), and matrix metalloproteinase 13 (MMP13), which are known to regulate cell migration and invasion. Our findings were further corroborated by analyzing the Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) dataset. We conclude that ILK promotes glioblastoma cell invasion through activation of ROCK1 and FSCN1 in vitro, providing a more exact molecular mechanism for its action.
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑肿瘤，其生存率较差。整合素连接激酶（ILK）是一种丝氨酸/苏氨酸蛋白拟激酶，与β1和β3 整合素的细胞质结构域结合，先前已被证明可促进许多癌症类型的侵袭和转移，包括 GBM。然而，关于 ILK 如何确切地促进 GBM 的侵袭性，人们知之甚少。在这项研究中，我们使用了两种脑细胞系，非侵袭性神经胶质瘤 H4 细胞和高度侵袭性的胶质母细胞瘤 A172 细胞，它们表达的 ILK 水平比 H4 高得多。我们研究了 ILK 沉默对体外 GBM 细胞转移行为的影响，并阐明了潜在的分子机制。我们发现，ILK 的 siRNA 介导沉默抑制了高度侵袭性 A172 细胞的迁移和侵袭，而不影响 H4 细胞的迁移和侵袭能力。这些数据还得到 Rho 相关激酶 1（ROCK1）、Fascin 肌动蛋白束蛋白 1（FSCN1）和基质金属蛋白酶 13（MMP13）表达变化的支持，这些蛋白已知可调节细胞迁移和侵袭。我们通过分析癌症基因组图谱胶质母细胞瘤多形性（TCGA-GBM）数据集进一步证实了这一发现。我们得出结论，ILK 通过体外激活 ROCK1 和 FSCN1 促进胶质母细胞瘤细胞侵袭，为其作用提供了更确切的分子机制。
