Abstract
Glioblastoma (GBM) is the most aggressive primary intracranial tumor of adults and confers a poor prognosis due to high vascularization. Hence anti-angiogenic therapy has become a promising strategy for GBM treatment. In this study, the transcription factor nuclear factor of activated T-cells 5 (NFAT5) was significantly elevated in glioma samples and GBM cell lines, and positively correlated with glioma WHO grades. Knockdown of NFAT5 inhibited GBM cell-driven angiogenesis. Furthermore, long non-coding RNA SBF2 antisense RNA 1 (SBF2-AS1) was upregulated in glioma samples and knockdown of SBF2-AS1 impaired GBM-induced angiogenesis. Downregulation of NFAT5 decreased SBF2-AS1 expression at transcriptional level. In addition, knockdown of SBF2-AS1 repressed GBM cell-driven angiogenesis via enhancing the inhibitory effect of miR-338-3p on EGF like domain multiple 7 (EGFL7). In vivo study demonstrated that the combination of NFAT5 knockdown and SBF2-AS1 knockdown produced the smallest xenograft volume and the lowest microvessel density. NFAT5/SBF2-AS1/miR-338-3p/EGFL7 pathway may provide novel targets for glioma anti-angiogenic treatment.
Highlights
Glioblastoma (GBM) harbors the highest malignancy of glioma
Immunohistochemistry results showed that normal brain tissues (NBTs) presented weak nuclear factor of activated T-cells 5 (NFAT5) staining
The proportion of NFAT5positive cells and the staining intensity were higher in glioma sections (Figure 1A) and presented a tumor pathological grade-dependent pattern (Figure 1B)
Summary
Glioblastoma (GBM) harbors the highest malignancy of glioma. Despite improvements in therapeutic management, the overall prognosis has remained dismal, with a median survival ranging from 12 to 15 months (Wen and Kesari, 2008). GBM is characterized by its profound vascularization. Deregulated pro-angiogenic factors were produced by GBM cells and secreted into the tumor microenvironment, which stimulates tumor endothelial cell-dependent angiogenesis. Neovascularity brings essential oxygen and nutrition as well as promotes GBM malignancy (Jain et al, 2007). Previous study manifested that microvessel density predicts poor prognosis of glioma
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