Abstract
Malignant glioma is one of the most lethal cancers with rapid progression, high recurrence, and poor prognosis in the central nervous system. Fatty acid-binding protein 6 (FABP6) is a bile acid carrier protein that is overexpressed in colorectal cancer. This study aimed to assess the involvement of FABP6 expression in the progression of malignant glioma. Immunohistochemical analysis revealed that FABP6 expression was higher in glioma than in normal brain tissue. After the knockdown of FABP6, a decrease in the migration and invasion abilities of glioma cells was observed. The phosphorylation of the myosin light chain was inhibited, which may be associated with migration ability. Moreover, expression levels of invasion-related proteins, matrix metalloproteinase-2 (MMP-2) and cathepsin B, were reduced. Furthermore, tube formation was inhibited in the human umbilical vein endothelial cells with a decreased concentration of vascular endothelial growth factor (VEGF) in the conditioned medium after the knockdown of FABP6. The phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p65 were also decreased after FABP6 reduction. Finally, the bioluminescent images and immunostaining of MMP-2, cluster of differentiation 31 (CD31), and the VEGF receptor 1 (VEGFR1) revealed attenuated tumor progression in the combination of the FABP6-knocked-down and temozolomide (TMZ)-treated group in an orthotopic xenograft mouse tumor model. This is the first study that revealed the impact of FABP6 on the invasion, angiogenesis, and progression of glioma. The results of this study show that FABP6 may be a potential therapeutic target combined with TMZ for malignant gliomas.
Highlights
Gliomas account for the majority of primary tumors that arise within the brain parenchyma and are the most common intracranial neoplasms [1]
The expression of Fatty acid-binding protein 6 (FABP6) was found to be elevated in the neoplastic brain tissue and was not proportional to the grade of the glioma
The addition of VEGFA reversed the tube formation ability in shFABP6 group (Figure S3). These results indicated that the angiogenic ability of endothelial cells was decreased by FABP6 knockdown in glioma cells, which might be due to the decrease in vascular endothelial growth factor (VEGF) secretion in glioma cells
Summary
Gliomas account for the majority of primary tumors that arise within the brain parenchyma and are the most common intracranial neoplasms [1]. The initial treatment for high-grade gliomas is surgical resection, if accessible, combined with adjuvant post-operative temozolomide (TMZ)-based chemoradiotherapy. Due to the infiltration of tumor cells, complete resection and adjuvant therapy are elusive, resulting in a higher percentage of recurrence and worse prognosis in patients with high-grade gliomas than in patients with low-grade gliomas [3]. Fatty acid-binding proteins (FABPs) modulate the metabolism of fatty acids, cell growth, and proliferation. In hepatocellular carcinoma (HCC), the upregulated fatty acid-binding protein 1 (FABP1) interacts with the VEGF receptor and Src via the focal adhesion kinase (FAK) and enhances the expression of the angiogenic vascular endothelial growth factor A (VEGF-A) [6]. FABP4 promotes tumor progression by altering the activities of matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, in prostate cancer [7]
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