Multiple formin proteins participate in glioblastoma migration

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

FHOD1 and FMNL1 formin proteins in intestinal gastric cancer: correlation with tumor-infiltrating T lymphocytes and molecular subtypes

“…These results indicate that FMNL1 may have a role in GC tumor progression. A similar association has been seen in other cancers [8,27].…”

“…We chose cell lines representing well differentiated (MKN28) and poorly differentiated (AGS, MKN45) GC. The cell stainings showed typical dot-like expression patterns and cytoplasmic location along the actin filaments, which have been previously reported in other cancer cell types [7,8,20]. This cytoplasmic pattern was recapitulated in the gastric cancer tissue samples, further confirming the integrity of the immunohistochemical stainings.…”

“…Formin homology two domain-containing protein one or FHOD1, is a crucial regulator of cellular actin dynamics [6]. Previous studies by us and others implicate FHOD1 as an essential participant in cancer cell migration, invasion, and stress fiber formation [7][8][9][10]. FHOD1 has been implicated as one of the crucial genes linked with advanced disease and metastasis in GC patients [11].…”

Preliminary Investigation on the Involvement of Cytoskeleton-Related Proteins, DAAM1 and PREP, in Human Testicular Disorders

“…Thus, considering this last point, and the fact that this is the first study indicating the correlation between the upregulated DAAM1 protein level and CS, it may be assumed that the involvement of this formin in the cellular events leading to neoplastic transformation. However, in this context, the role of other formins cannot to be excluded, since it has been previously demonstrated that the up-regulation of many of these family members, such as mDia, DIAPH1, and FMNL, has been positively correlated to cancer progression [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Therefore, the study of such proteins in CS may be of great interest, but it is beyond the scope of this paper, which is exclusively focused on DAAM1.…”

Clonal Evolution of a High-Grade Pediatric Glioma With Distant Metastatic Spread

“… 15 Its effect could be synergistic with the mutation of the formin FHOD1, also involved in migration of glioma cells in vitro . 16 , 17 …”