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Knockdown of USF1 Inhibits the Vasculogenic Mimicry of Glioma Cells via Stimulating SNHG16/miR-212-3p and linc00667/miR-429 Axis.

ABSTRACT: The anti-angiogenic treatment of malignant glioma cells is an effective method to treat high-grade gliomas. However, due to the presence of vasculogenic mimicry (VM), the anti-angiogenic treatment of gliomas is not significantly effective in improving overall patient median survival. Therefore, this study investigated the mechanism of mimic formation of angiogenesis in gliomas. The results of this experiment indicate that the expression of upstream transcription factor 1 (USF1) is upregulated in glioma tissues and cells. USF1 knockdown inhibits the proliferation, migration, invasion, VM, and expression of VM-associated proteins in glioma cells by stimulating SNHG16 and linc00667. These two long non-coding RNAs (lncRNAs) regulate ALHD1A1 through the competing endogenous RNA (ceRNA) mechanism influencing the VM of glioma. This study is the first to demonstrate that the USF1/SNHG16/miR-212-3p/ALDH1A1 (aldehyde dehydrogenase-1) and USF1/linc00667/miR-429/ALDH1A1 axis regulates the VM of glioma cells, and these findings might provide a novel strategy for glioma treatment.

SUBMITTER: Wang D

PROVIDER: S-EPMC6369224 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Knockdown of USF1 Inhibits the Vasculogenic Mimicry of Glioma Cells via Stimulating SNHG16/miR-212-3p and linc00667/miR-429 Axis.

Wang Di D Zheng Jian J Liu Xiaobai X Xue Yixue Y Liu Libo L Ma Jun J He Qianru Q Li Zhen Z Cai Heng H Liu Yunhui Y

Molecular therapy. Nucleic acids 20190115

The anti-angiogenic treatment of malignant glioma cells is an effective method to treat high-grade gliomas. However, due to the presence of vasculogenic mimicry (VM), the anti-angiogenic treatment of gliomas is not significantly effective in improving overall patient median survival. Therefore, this study investigated the mechanism of mimic formation of angiogenesis in gliomas. The results of this experiment indicate that the expression of upstream transcription factor 1 (USF1) is upregulated in ...[more]

PMID: 30743215

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Project description:Rationale: Glioma is the most common primary malignant tumor of human central nervous system, and its rich vascular characteristics make anti-angiogenic therapy become a therapeutic hotspot. However, the existence of glioma VM makes the anti-angiogenic therapy ineffective. SUMOylation is a post-translational modification that affects cell tumorigenicity by regulating the expression and activity of substrate proteins. Methods: The binding and modification of IGF2BP2 and SUMO1 were identified using Ni2+-NTA agarose bead pull-down assays, CO-IP and western blot; and in vitro SUMOylation assays combined with immunoprecipitation and immunofluorescence staining were performed to explore the detail affects and regulations of the SUMOylation on IGF2BP2. RT-PCR and western blot were used to detect the expression levels of IGF2BP2, OIP5-AS1, and miR-495-3p in glioma tissues and cell lines. CCK-8 assays, cell transwell assays, and three-dimensional cell culture methods were used for evaluating the function of IGF2BP2, OIP5-AS1, miR-495-3p, HIF1A and MMP14 in biological behaviors of glioma cells. Meantime, RIP and luciferase reporter assays were used for inquiring into the interactions among IGF2BP2, OIP5-AS1, miR-495-3p, HIF1A and MMP14. Eventually, the tumor xenografts in nude mice further as certained the effects of IGF2BP2 SUMOylation on glioma cells. Results: This study proved that IGF2BP2 mainly binds to SUMO1 and was SUMOylated at the lysine residues K497, K505 and K509 sites, which can be reduced by SENP1. SUMOylation increased IGF2BP2 protein expression and blocked its degradation through ubiquitin-proteasome pathway, thereby increasing its stability. The expressions of IGF2BP2 and OIP5-AS1 were up-regulated and the expression of miR-495-3p was down-regulated in both glioma tissues and cells. IGF2BP2 enhances the stability of OIP5-AS1, thereby increasing the binding of OIP5-AS1 to miR-495-3p, weakening the binding of miR-495-3p to the 3'UTR of HIF1A and MMP14 mRNA, and ultimately promoting the formation of VM in glioma. Conclusions: This study first revealed that SUMOylation of IGF2BP2 regulated OIP5-AS1/miR-495-3p axis to promote VM formation in glioma cells and xenografts growth in nude mice, providing a new idea for molecular targeted therapy of glioma.

Project description:In recent decades, antiangiogenic therapy, which blocks the supply of oxygen and nutrition to tumor cells, has become a promising clinical strategy for the treatment of patients with tumors. However, recent studies revealed that vasculogenic mimicry (VM), which is the process by which vascular morphological structures are formed by highly invasive tumor cells, has been considered a potential factor for the failure of antiangiogenic therapy in patients with tumors. Thus, inhibition of VM formation might be a potential target for improving the outcome of antiangiogenic strategies. However, the mechanism underlying VM formation is still incompletely elucidated. Herein, we report that L1CAM might be a critical regulator of VM formation in glioma, and might be associated with the resistance of glioma to antiangiogenic therapy. We found that the tumor-invasion and tube-formation capabilities of L1CAM-overexpressing cells were significantly enhanced in vitro and in vivo. In addition, the results indicated that miR-143-3p, which might directly target the 3'UTR of the hexokinase 2 (HK2) gene to regulate its protein expression, was subsequently involved in L1CAM-mediated VM formation by glioma cells. Further study revealed that the regulation of MMP2, MMP9, and VEGFA expression was involved in this process. Moreover, we identified that activation of the downstream PI3K/AKT signaling pathway of the L1CAM/HK2 cascade is critical for VM formation by glioma cells. Furthermore, we found that the combined treatment of anti-L1CAM neutralizing monoclonal antibody and bevacizumab increases efficacy beyond that of bevacizumab alone, and suppresses glioma growth in vivo, indicating that the inhibition of L1CAM-mediated VM formation might efficiently improve the effect of antiangiogenic treatment for glioma patients. Together, our findings demonstrated a critical role of L1CAM in regulating VM formation in glioma, and that L1CAM might be a potential target for ameliorating tumor resistance to antiangiogenic therapy in glioma patients.

Dataset Information

Knockdown of USF1 Inhibits the Vasculogenic Mimicry of Glioma Cells via Stimulating SNHG16/miR-212-3p and linc00667/miR-429 Axis.

Publications

Knockdown of USF1 Inhibits the Vasculogenic Mimicry of Glioma Cells via Stimulating SNHG16/miR-212-3p and linc00667/miR-429 Axis.

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