Abstract
BackgroundThe 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.MethodsIn 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.ResultsWe 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.ConclusionsFormins 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.
Highlights
The prognosis of glioblastoma remains poor, related to its diffuse spread within the brain
Inverted formin 2 (INF2) and Formin homology domain containing protein 1 (FHOD1) are upregulated in migrating glioblastoma cells To investigate the expression profiles of formins in glioblastoma, we studied the mRNA expression of all 15 formin genes in five different patient-derived glioblastoma cell lines
The cell lines had been subjected to a spheroid migration experiment, followed by transcriptomic analysis of migrating cells and spheroids [2, 16]
Summary
The prognosis of glioblastoma remains poor, related to its diffuse spread within the brain. One approach is to look for actin regulating proteins that might be targeted by future anti-cancer therapy. The formin proteins mDia and mDia 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. Recent studies have shown that migrating cells infiltrating the brain express stem cell markers [2]. Cells outside the tumor bulk may be connected by microtubes, forming a network of infiltrative cells that contribute to this resistance to treatment [5, 6]. In order to target infiltrating cells, more knowledge about their cell biology is needed
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