Laboratory Division, Department of Pathology, Turku University Hospital, Turku, Finland.
Institute of Biomedicine, University of Turku, Turku, Finland.
BMC Cancer. 2020 Jul 29;20(1):710. doi: 10.1186/s12885-020-07211-7.
The prognosis of glioblastoma remains poor, related to its diffuse spread within the brain. There is an ongoing search for molecular regulators of this particularly invasive behavior. One approach is to look for actin regulating proteins that might be targeted by future anti-cancer therapy. The formin family of proteins orchestrates rearrangement of the actin cytoskeleton in multiple cellular processes. Recently, the formin proteins mDia1 and mDia2 were shown to be expressed in glioblastoma in vitro, and their function could be modified by small molecule agonists. This finding implies that the formins could be future therapeutic targets in glioblastoma.
In cell studies, we investigated the changes in expression of the 15 human formins in primary glioblastoma cells and commercially available glioblastoma cell lines during differentiation from spheroids to migrating cells using transcriptomic analysis and qRT-PCR. siRNA mediated knockdown of selected formins was performed to investigate whether their expression affects glioblastoma migration. Using immunohistochemistry, we studied the expression of two formins, FHOD1 and INF2, in tissue samples from 93 IDH-wildtype glioblastomas. Associated clinicopathological parameters and follow-up data were utilized to test whether formin expression correlates with survival or has prognostic value.
We found that multiple formins were upregulated during migration. Knockdown of individual formins mDia1, mDia2, FHOD1 and INF2 significantly reduced migration in most studied cell lines. Among the studied formins, knockdown of INF2 generated the greatest reduction in motility in vitro. Using immunohistochemistry, we demonstrated expression of formin proteins FHOD1 and INF2 in glioblastoma tissues. Importantly, we found that moderate/high expression of INF2 was associated with significantly impaired prognosis.
Formins FHOD1 and INF2 participate in glioblastoma cell migration. Moderate/high expression of INF2 in glioblastoma tissue is associated with worse outcome. Taken together, our in vitro and tissue studies suggest a pivotal role for INF2 in glioblastoma. When specific inhibiting compounds become available, INF2 could be a target in the search for novel glioblastoma therapies.
胶质母细胞瘤的预后仍然很差，这与其在大脑内弥漫性扩散有关。目前正在寻找这种特别侵袭性行为的分子调节剂。一种方法是寻找可能成为未来抗癌治疗靶点的肌动蛋白调节蛋白。formin 蛋白家族在多种细胞过程中协调肌动蛋白细胞骨架的重排。最近，formin 蛋白 mDia1 和 mDia2 在体外被证明存在于胶质母细胞瘤中，其功能可以通过小分子激动剂进行修饰。这一发现表明 formin 蛋白可能成为胶质母细胞瘤的未来治疗靶点。
在细胞研究中，我们使用转录组分析和 qRT-PCR 研究了原发性胶质母细胞瘤细胞和市售胶质母细胞瘤细胞系在从球体分化为迁移细胞过程中 15 种人类 formin 蛋白的表达变化。通过 siRNA 介导的敲低选定的 formin 蛋白，研究其表达是否影响胶质母细胞瘤的迁移。使用免疫组织化学方法，我们研究了 93 例 IDH 野生型胶质母细胞瘤组织样本中两种 formin 蛋白 FHOD1 和 INF2 的表达。利用相关的临床病理参数和随访数据，检验 formin 表达是否与生存相关或具有预后价值。
我们发现，在迁移过程中，多种 formin 蛋白上调。在大多数研究的细胞系中，敲低单个 formin mDia1、mDia2、FHOD1 和 INF2 显著降低了迁移。在所研究的 formin 蛋白中，INF2 的敲低在体外产生了最大的运动性降低。使用免疫组织化学方法，我们证明了 formin 蛋白 FHOD1 和 INF2 在胶质母细胞瘤组织中的表达。重要的是，我们发现 INF2 的中度/高表达与显著的预后不良相关。
formin 蛋白 FHOD1 和 INF2 参与胶质母细胞瘤细胞迁移。胶质母细胞瘤组织中 INF2 的中度/高表达与预后不良相关。综上所述，我们的体外和组织研究表明 INF2 在胶质母细胞瘤中起着关键作用。当特定的抑制化合物可用时，INF2 可能成为寻找新的胶质母细胞瘤治疗方法的靶点。
