Abstract
Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in these processes. However, the role of formin-like 1 (FMNL1) in cancer remains unclear. We studied FMNL1 expression in glioblastoma samples using immunohistochemistry. We sought to analyze the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from The Cancer Genome Atlas and analyzed using gene set enrichment analysis (GSEA). FMNL1 was an independent predictor of poor prognosis in a cohort of 217 glioblastoma multiforme cases (p < 0.001). FMNL1 expression was significantly higher in the mesenchymal subtype. FMNL1 upregulation and downregulation were associated with mesenchymal and proneural markers in the GSEA, respectively. These data highlight the important role of FMNL1 in the neural-to-mesenchymal transition. Conversely, FMNL1 downregulation suppressed glioblastoma multiforme cell migration and invasion via DIAPH1 and GOLGA2, respectively. FMNL1 downregulation also suppressed actin fiber assembly, induced morphological changes, and diminished filamentous actin. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression.
Highlights
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and is classified as grade IV by the World Health Organization (WHO)
formin-like 1 (FMNL1) levels were associated with age (p = 0.006), Karnofsky performance status (KPS; p = 0.039), extent of surgical resection (p = 0.01), and number of surgeries (p < 0.001)
The gene set enrichment analysis (GSEA) of GBM cases in The Cancer Genome Atlas (TCGA) identified the gene sets GO_LAMELLIPODIUM, KEGG_FOCAL_ADHESION, GO_INVADOPODIUM, BUDHU_LIVER_CANCER_METASTASIS_UP, CROMER_METASTASIS_UP, CELL_MIGRATION, WU_CELL_MIGRATION, GO_ACTIN_CYTOSKELETON, and GO_ACTIN_FILAMENT_POLYMERIZATION as being significantly associated with FMNL1 expression (Figure S5)
Summary
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and is classified as grade IV by the World Health Organization (WHO). Formin proteins have been implicated in cancer progression, invasion, and migration. FMNL1 is naturally enriched in hematopoietic cells and tissues such as thymus, spleen, and peripheral blood leukocytes. It is overexpressed in malignant lymphomas in patients with chronic lymphocytic leukemia, as well as in T cells in patients with malignant non-Hodgkin’s lymphoma [9,10]. The role of FMNL1 in GBM is unclear [11], formin-related proteins have been implicated in the pathophysiology of several other tumors. FMNL3 promotes migration, proliferation, and metastasis in colorectal cancer, melanoma, esophageal squamous cell carcinoma, and nasopharyngeal carcinoma [16,17,18]. FMNL1, FMNL2, and FMNL3 are correlated with poor prognosis in several cancers [12,13,14,15,16,17,18]
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