MiR-9 Promotes Angiogenesis via Targeting on Sphingosine-1- Phosphate Receptor 1

Abstract

We previously demonstrated that vascular endothelial cells released VEGF-enriched exosomes to promote the tumor vasculogenesis and progression after anti-angiogenic therapies (AATs). To clarify how microRNA (miR)-9 promoted the angiogenesis of tumorassociated endothelial cells, in the present study, we investigated the association between miR-9 and sphingosine-1-phosphate (S1P) receptors in angiogenesis. The levels of miR-9 and S1P receptors in normal and tumor endothelial cells were compared with EndoDB database and their correlations were analyzed. The levels of S1P 1 , S1P 2 , and S1P 3 were detected in miR-9 overexpressing endothelial cells by qRT-PCR and western blot. The binding sites of miR-9 on S1P 1 and S1P 3 were predicted and tested by dual-luciferase reporter assays. Then, angiogenesis in endothelial cells overexpressing both S1P 1 and miR-9 was detected. The results showed that miR-9 is overexpressed in ECs from medulloblastoma and glioblastoma xenograft, which is negatively associated with S1P 1 and S1P 3. Overexpression of miR-9 significantly inhibited S1P 1 and S1P 3 in both mRNA and protein levels. We predicted that binding sites exist between miR-9 and S1P 1 , S1P 3 , but only S1P 1 was directly targeted by miR-9. Overexpression of S1P 1 significantly suppressed the miR-9-induced angiogenesis. Therefore, miR-9 induces angiogenesis via targeting on S1P 1 .

Therapeutic Potential of Exosomes in Pulmonary Fibrosis

“…MiRNAs are major components of exosomes (Zeng et al, 2019). These molecules can bind to and regulate target mRNAs by inhibiting their translation or promoting their degradation and are widely involved in cell proliferation, apoptosis, development, differentiation, angiogenesis, and fibrosis (Kadota et al, 2020;Yao et al, 2020). Exosomes secreted by cancer-related fibroblasts and harboring miR-21, mir-378e and miR-143 can induce EMT in different breast cancer cell lines, and miR-21 can also promote EMT in renal tubular epithelial cells (Donnarumma et al, 2017).…”

Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

“…Improves AATs resistance by releasing VEGF-enriched exosomes in HCC (Zeng et al, 2019). Promotes angiogenesis via targeting S1P 1 (Yao et al, 2020).…”

“…miR-9 is rich in HCC tissues and tumor-cocultured ECs, while the miR-9 was lowly expressed in normal ECs ( Zhuang et al, 2012 ; Zeng et al, 2019 ). miR-9-2 was significantly higher in ECs from Wnt- and Shh-medulloblastoma and glioblastoma xenograft than in normal ECs ( Yao et al, 2020 ). The G protein-coupled sphingosine-1-phosphate (S1P) receptor one S1P 1 was significantly lower in ECs from Wnt-medulloblastoma, secondary colorectal cancer, and HCC than in normal ECs, and negatively correlated to miR-9-2 in Shh-medulloblastoma ECs ( Yao et al, 2020 ).…”

“…miR-9-2 was significantly higher in ECs from Wnt- and Shh-medulloblastoma and glioblastoma xenograft than in normal ECs ( Yao et al, 2020 ). The G protein-coupled sphingosine-1-phosphate (S1P) receptor one S1P 1 was significantly lower in ECs from Wnt-medulloblastoma, secondary colorectal cancer, and HCC than in normal ECs, and negatively correlated to miR-9-2 in Shh-medulloblastoma ECs ( Yao et al, 2020 ). S1P 1 has been found to control the sorting of cargo into exosomes derived from ECs and tumor cells ( Kajimoto et al, 2013 ).…”

“…Angiogenesis is regulated by hypoxia, low pH, high pressure as well as a large number of growth factors and proteolytic enzymes in the tumor microenvironment. In addition, microRNA (miR)-9 is enriched in tumor ECs, and it promotes angiogenesis ( Zeng et al, 2019 ; Yao et al, 2020 ). Although AATs suppress the angiogenesis of tumor ECs at the primary site, they trigger VEGF-enriched exosomes released from tumor ECs to facilitate the tumor vasculogenesis for relapse ( Zeng et al, 2019 ).…”