LOXL1-AS1 communicating with TIAR modulates vasculogenic mimicry in glioma via regulation of the miR-374b-5p/MMP14 axis.
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ABSTRACT:
SUBMITTER: Yi B
PROVIDER: S-EPMC8743654 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Increasing evidence has suggested that gliomas can supply blood through vasculogenic mimicry. In this study, the expression and function of ZNRD1-AS1-144aa-uORF (144aa-uORF) and some non-coding RNAs in gliomas were assessed. Real-time quantitative PCR or Western blot was used to discover the expression of 144aa-uORF, ZNRD1-AS1, miR-499a-5p, ELF1 and EMI1 in gliomas. In addition, RIP and RNA pull-down assays were applied to explore the interrelationship between 144aa-uORF and ZNRD1-AS1. The role of the 144aa-uORF\ZNRD1-AS1\miR-499a-5p\ELF1\EMI1 axis in vasculogenic mimicry formation of gliomas was analysed. This study illustrates the reduced expression of the 144aa-uORF in glioma tissues and cells. Up-regulation of 144aa-uORF inhibits proliferation, migration, invasion and vasculogenic mimicry formation within glioma cells. The up-regulated 144aa-uORF can increase the degradation of ZNRD1-AS1 through the nonsense-mediated RNA decay (NMD) pathway. Knockdown of ZNRD1-AS1 inhibits vasculogenic mimicry in glioma cells by modulating miR-499a-5p. At the same time, miR-499a-5p is down-regulated and has a tumour-suppressive effect in gliomas. In addition, ZNRD1-AS1 serves as a competitive endogenous RNA (ceRNA) and regulates the expression of ELF1 by binding to miR-499a-5p. Notably, ELF1 binds to the promoter region of EMI1 and up-regulates EMI1 expression, while simultaneously promoting vasculogenic mimicry in glioma cells. This study suggests that the 144aa-uORF\ZNRD1-AS1\miR-499a-5p\ELF1\EMI1 axis takes key part in regulating the formation of vasculogenic mimicry in gliomas and may provide a potential target for glioma treatment.
| S-EPMC7294115 | biostudies-literature
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.
| S-EPMC8326132 | biostudies-literature
Project description:Gliomas are among the most lethal primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic mimicry. With suspension microarray technology and in vitro tube formation assays, we identified that astrocytes relied on TGF-β1 to enhance vasculogenic mimicry. We also found that vasculogenic mimicry was inhibited by galunisertib, a promising TGF-β1 inhibitor currently being studied in an ongoing trial in glioma patients. The inhibition was partially attributed to a decrease in autophagy after galunisertib treatment. Moreover, we observed a decrease in VE-cadherin and smooth muscle actin-α expression, as well as down-regulation of Akt and Flk phosphorylation in galunisertib-treated glioma cells. By comparing tumor weight and volume in a xenograft model, we acquired promising results to support our theory. This study expands our understanding of the role of astrocytes in gliomas and demonstrates that galunisertib inhibits glioma vasculogenic mimicry induced by astrocytes.
| S-EPMC4791658 | biostudies-other
Project description:BackgroundGlioma is the most common intracranial neoplasm with vasculogenic mimicry formation as one form of blood supply. Many RNA-binding proteins and long non-coding RNAs are involved in tumorigenesis of glioma.MethodsThe expression of ZRANB2, SNHG20 and FOXK1 in glioma were detected by real-time PCR or western blot. The function of ZRANB2/SNHG20/FOXK1 axis in glioma associated with vasculogenic mimicry formation was analyzed.ResultsZRANB2 is up-regulated in glioma tissues and glioma cells. ZRANB2 knockdown inhibits the proliferation, migration, invasion and vasculogenic mimicry formation of glioma cells. ZRANB2 binds to SNHG20 and increases its stability. Knockdown of SNHG20 reduces the degradation of FOXK1 mRNA by SMD pathway. FOXK1 inhibits transcription by binding to the promoters of MMP1, MMP9 and VE-Cadherin and inhibits vasculogenic mimicry formation of glioma cells.ConclusionsZRANB2/SNHG20/FOXK1 axis plays an important role in regulating vasculogenic mimicry formation of glioma, which might provide new targets of glioma therapy.
| S-EPMC6371528 | biostudies-literature
Project description:Vasculogenic mimicry (VM) has been reported to accelerate angiogenesis in malignant tumors, yet the mechanism underlying VM has not been fully elucidated. N6-methyladenosine (m6A) mainly modulates mRNA fate and affects multiple tumorigenesis. Here, we aimed to investigate m6A-modified HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) in the regulation of glioma-associated VM formation. Gene expression was analyzed by quantitative RT-PCR. Cell viability, metastases, and VM formation capacity were determined by CCK-8, migration and invasion, as well as tube formation assays, respectively. The function and mechanisms of m6A-modified HOTAIRM1 were defined through liquid chromatography-tandem mass spectrometry m6A quantification, methylated RNA immunoprecipitation sequencing, RNA stability assays, and RNA pull-down experiments. A glioma xenograft mouse model was further established for VM evaluation in vivo. The results showed that HOTAIRM1, methyltransferase-like 3 (METTL3), and insulin-like growth factor binding protein 2 (IGFBP2) were upregulated in glioma tissues and cell lines. HOTAIRM1 functions as an oncogene in glioma progression; however, knockdown of HOTAIRM1 significantly reduced cell viability, migration, invasion, and VM formation. Notably, METTL3-dependent m6A modification enhanced HOTAIRM1 mRNA stability, whereas knockdown of METTL3 deficiency significantly suppressed VM in glioma. Moreover, HOTAIRM1 was found to bind IGFBP2, and HOTAIRM1 deficiency blocked glioma progression and VM formation in vivo. Our results indicated that METTL3-dependent m6A-modified HOTAIRM1 promoted VM formation in glioma.
| S-EPMC9807531 | biostudies-literature
Project description:Vasculogenic mimicry (VM), the formation of vessel-like structures by highly invasive tumor cells, has been considered one of several mechanisms responsible for the failure of anti-angiogenesis therapy in glioma patients. Therefore, inhibiting VM formation might be an effective therapeutic method to antagonize the angiogenesis resistance. This study aimed to show that an extracellular protein called Tenascin-c (TNC) is involved in VM formation and that TNC knockdown inhibits VM in glioma. TNC was upregulated with an increase in glioma grade. TNC and VM formation are potential independent predictors of survival of glioma patients. TNC upregulation was correlated with VM formation, and exogenous TNC stimulated VM formation. Furthermore, TNC knockdown significantly suppressed VM formation and proliferation in glioma cells in vitro and in vivo, with a reduction in cellular invasiveness and migration. Mechanistically, TNC knockdown decreased Akt phosphorylation at Ser473 and Thr308 and subsequently downregulated matrix metalloproteinase 2 and 9, both of which are important proteins associated with VM formation and migration. Our results indicate that TNC plays an important role in VM formation in glioma, suggesting that TNC is a potential therapeutic target for anti-angiogenesis therapy for glioma.
| S-EPMC6872754 | biostudies-literature
Project description:AbstractVasculogenic mimicry (VM) is the formation of a “vessel-like” structure without endothelial cells. VM exists in vascular-dependent solid tumors and is a special blood supply source involved in the highly invasive tumor progression. VM is observed in a variety of human malignant tumors and is closely related to tumor proliferation, invasion, and recurrence. Here, we review the mechanism, related signaling pathways, and molecular regulation of VM in glioma and discuss current research problems and the potential future applications of VM in glioma treatment. This review may provide a new viewpoint for glioma therapy.
| S-EPMC7247597 | biostudies-literature
Project description:Glioma is the most common form of primary central nervous malignant tumors. Vasculogenic mimicry (VM) is a blood supply channel that is different from endothelial blood vessels in glioma. VM is related to tumor invasion and metastasis. Therefore, it plays an important role to target therapy for glioma VM. Our experimental results showed abnormal expression of UBE2I, PUM2, CEBPD, and DSG2 in glioma cells. The Co-IP and Immunofluorescence staining were used to detect that PUM2 can be modified by SUMO2/3. The interaction between PUM2 and CEBPD mRNA was detected by the RIP assays. The interaction between transcription factor CEBPD and promoter region of DSG2 was detected by the ChIP assays and luciferase assays. The capacity for migration in glioma cells was observed by the laser holographic microscope. The capacity for invasion in glioma cells was detected by Transwell method. The VM in glioma cells was detected by three-dimensional cell culture method. The experimental results found that the upregulation of UBE2I in glioma tissues and cells promotes the SUMOylation of PUM2, which decreases not only the stability of PUM2 protein but also decreases the inhibitory effect of PUM2 on CEBPD mRNA. The upregulation of CEBPD promotes the binding to the upstream promoter region of DSG2 gene, further upregulates the expression of DSG2, and finally promotes the development of glioma VM. In conclusion, this study found that the UBE2I/PUM2/CEBPD/DSG2 played crucial roles in regulating glioma VM. It also provides potential targets and alternative strategies for combined treatment of glioma.
| S-EPMC7507322 | biostudies-literature
Project description:Like the anti-angiogenic strategy, anti-vascular mimicry is considered as a novel targeting strategy for glioma. In the present study, we used NGR as a targeting ligand and prepared NGR-modified liposomes containing combretastatin A4 (NGR-SSL-CA4) in order to evaluate their potential targeting of glioma tumor cells and vasculogenic mimicry (VM) formed by glioma cells as well as their anti-VM activity in mice with glioma tumor cells. NGR-SSL-CA4 was prepared by a thin-film hydration method. The in vitro targeting of U87-MG (human glioma tumor cells) by NGR-modified liposomes was evaluated. The in vivo targeting activity of NGR-modified liposomes was tested in U87-MG orthotopic tumor-bearing nude mice. The anti-VM activity of NGR-SSL-CA4 was also investigated in vitro and in vivo. The targeting activity of the NGR-modified liposomes was demonstrated by in vitro flow cytometry and in vivo biodistribution. The in vitro anti-VM activity of NGR-SSL-CA4 was indicated in a series of cell migration and VM channel experiments. NGR-SSL-CA4 produced very marked anti-tumor and anti-VM activity in U87-MG orthotopic tumor-bearing mice in vivo. Overall, the NGR-SSL-CA4 has great potential in the multi-targeting therapy of glioma involving U87-MG cells, and the VM formed by U87-MG cells as well as endothelial cells producing anti-U87-MG cells, and anti-VM formed by U87-MG cells as well as anti-endothelial cell activity.
| S-EPMC5190048 | biostudies-literature
Project description:Background:Gastric cancer (GC) is a deadly disease, and its incidence is especially high in East Asia including China. Recently, some long non-coding RNA (lncRNAs) have been identified as oncogenes or tumor suppressors. This study aimed to determine the function and mechanism of lncRNA LOXL1-AS1 on the progression of GC. Methods:RT-PCR was done to measure the expression levels of LOXL1-AS1 and miR-142-5p in GC tissues. The association between pathological indexes and LOXL1-AS1 expression was also analyzed. Human GC cell lines AGS and BGC823 were used as cell models. CCK-8 and colony formation assays were conducted to assess the effect of LOXL1-AS1 on the proliferation of GC cell lines. Transwell assay was conducted to determine the influence of LOXL1-AS1 on cell migration and invasion. Furthermore, luciferase reporter assay was carried out to confirm the relationship of miR-142-5p with LOXL1-AS1. Additionally, Western blot was done to detect the regulatory function of LOXL1-AS1 on PIK3CA, a target of miR-142-5p. In vivo experiment was also performed to validate the roles and mechanism of LOXL1-AS1 on the growth and metastasis of GC cells. Results:LOXL1-AS1 expression in GC samples was significantly increased, which was correlated with unfavorable pathological indexes. Highly expressed LOXL1-AS1 was closely linked to shorter overall survival time and post-progression survival time of the patients. LOXL1-AS1 markedly modulated the malignant phenotypes of GC cells. Additionally, overexpressed LOXL1-AS1 notably reduced the expression of miR-142-5p, but enhanced the expression level of PIK3CA. In vivo experiments further validated that knockdown of LOXL1-AS1 inhibited the growth and metastasis of GC cells via regulating miR-142-5p and PIK3CA. Conclusion:LOXL1-AS1 was a sponge of tumor suppressor miR-142-5p in GC, enhanced the expression of PIK3CA indirectly and functioned as an oncogenic lncRNA.
| S-EPMC6929932 | biostudies-literature