High filamin-C expression predicts enhanced invasiveness and poor outcome in glioblastoma multiforme

Abstract

Background Glioblastoma multiforme (GBM), the most common brain malignancy in adults, is generally aggressive and incurable, even with multiple treatment modalities and agents. Filamins (FLNs) are a group of actin-binding proteins that regulate the actin cytoskeleton in cells. However, the role of FLNs in malignancies—particularly in GBM—is unclear. Methods The relation between FLNC expression and overall survival in GBM was evaluated by the Kaplan−Meier analysis using GBM patients from the Kagoshima University Hospital ( n = 90) and data from the Cancer Genome Atlas (TCGA) ( n = 153). To assess FLNC function in GBM, cell migration and invasion were examined with Transwell and Matrigel invasion assays using FLNC-overexpressing U251MG and LN299 GBM cells, and ShRNA-mediated FLNC knocked-down KNS81 and U87MG cells. The gelatin zymography assay was used to estimate matrix metalloproteinase (MMP) 2 activity. Results In silico analysis of GBM patient data from TCGA and immunohistochemical analyses of clinical GBM specimens revealed that increased FLNC expression was associated with poor patient prognosis. FLNC overexpression in GBM cell lines was positively correlated with enhanced invasiveness, but not migration, and was accompanied by upregulation of MMP2. Conclusions FLNC is a potential therapeutic target and biomarker for GBM progression.

Clinical trajectory of a patient with filaminopathy who developed arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors

“…FLNs are involved in various signaling pathways; thus, a relationship between FLNs and tumor progression has been suggested [11], with evidence regarding the roles of FLNA and FLNB in cancer having been reported [22,23]. Although there are only a few reports showing the relationship between FLNC and tumor [11,12,14,19,21], the presence of multiorgan tumors in this case implies the possible relationship of FLNC mutation with tumorigenesis. Although accumulation of clinical data and future research is required to clarify the relationship, we should pay attention to the presence of tumors in the medical management of patients with FLNC myopathy.…”

“…The most notable finding in this case was the comorbidity of multiorgan tumors (urinary bladder and breast cancer) and a polyp (gastric fundic polyp). Recently, several reports have suggested an association between the dysregulation of FLNC and various tumors, such as prostate cancer [18,19], ovarian cancer [20], gastric cancer [12], urinary bladder [21], breast cancer [13], and glioblastoma [14]. One study reported that the variants of FLNC were found in 4% of invasive lobular breast cancers associated with CDH1 mutations [13].…”

“…Then, these proteins regulate the actin reorganization dependent process, such as cell migration, proliferation, and differentiation in different types of cells [11]. Recently, several papers have reported on the relationship between FLNC and tumors [11][12][13][14].…”

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

“… 13 FLNA is an actin-binding protein involved in cell motility and invasion of glioblastoma cells, 14 and its overexpression is associated with progression to metastasis and/or poor prognosis in several cancers. 15 Its effect could be synergistic with the mutation of the formin FHOD1, also involved in migration of glioma cells in vitro . 16 , 17 …”

Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

“…Although Filamin has been originally identified as a tumor promoting factor, prognostic value is mainly dependent on its subcellular localization and binding with different proteins [ 205 ]. High Filamin levels have been shown to be predictors of poor patient outcome in several tumors including melanoma, breast, and glioblastoma multiforme [ 206 ]. Whereas, the Filamin A isoform has been shown to inhibit tumor progression by regulating breast cancer type 1 susceptibility protein (BRCA1) expression in human breast cancer [ 207 ].…”