Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma
BackgroundOsteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. microRNAs have been found to play a vital role in tumor angiogenesis. Here, we investigated the effects of miR-199a-5p on tumor growth and angiogenesis in osteosarcoma. Furthermore, the underlying mol...
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.884559/full |
| _version_ | 1818206787140059136 |
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| author | Lu Zhang Hongxin Cao Hongxin Cao Guanghui Gu Dehui Hou Yunhao You Xiang Li Yunzhen Chen Guangjun Jiao |
| author_facet | Lu Zhang Hongxin Cao Hongxin Cao Guanghui Gu Dehui Hou Yunhao You Xiang Li Yunzhen Chen Guangjun Jiao |
| author_sort | Lu Zhang |
| collection | DOAJ |
| description | BackgroundOsteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. microRNAs have been found to play a vital role in tumor angiogenesis. Here, we investigated the effects of miR-199a-5p on tumor growth and angiogenesis in osteosarcoma. Furthermore, the underlying molecular mechanisms and signaling pathways were explored.MethodsThe datasets were extracted from the Gene Expression Omnibus and the differentially expressed miRNAs (DEmiRNAs) were screened out by the GEO2R online platform. The potential target genes were predicted using the miRTarBase database. The predicted target genes were further analyzed by Gene Ontology and pathway enrichment analysis and a regulatory network of DEmiRNAs and their target genes was constructed. In addition, the effects of osteosarcoma cell derived exosomal miR-199a-5p on the proliferation, migration and neovascularization of HUVECs were evaluated by conducting EdU assays, Transwell experiments and tube formation assays. A dual-luciferase reporter assay was performed to detect whether VEGFA was the direct target of miR-199a-5p. Furthermore, in vivo xenograft models were established to further investigate the intrinsic role of miR-199a-5p in osteosarcoma tumorigenesis and angiogenesis.ResultsA total of 149 DE-miRNAs were screened out, including 136 upregulated miRNAs and 13 downregulated miRNAs in human osteosarcoma plasma samples compared with normal plasma samples. A total of 1313 target genes of the top three upregulated and downregulated miRNAs were predicted. In the PPI network, the top 10 hub nodes with higher degrees were identified as hub genes, such as TP53 and VEGFA. By constructing the miRNA-hub gene network, we found that most of hub genes could be potentially modulated by miR-663a, miR-199a-5p and miR-223-3p. In addition, we found that the expression level of miR-199a-5p in exosomes derived from osteosarcoma cells was remarkably higher than the osteosarcoma cells, and the exosomes derived from osteosarcoma cells were transported to HUVECs. Overexpression of miR-199a-5p could significantly inhibited HUVEC proliferation, migration and neovascularization, whereas downregulation of miR-199a-5p expression exerted the opposite effect. Moreover, the in vivo results verified that overexpression of miR-199a-5p in osteosarcoma cells could suppress the growth and angiogenesis of tumors.ConclusionOur results demonstrated that miR-199a-5p could be transported from osteosarcoma cells to HUVECs through exosomes, subsequently targeting VEGFA and inhibiting the growth and angiogenesis of osteosarcoma. Therefore, miR-199a-5p may act as a biomarker in the diagnosis and treatment of osteosarcoma. |
| first_indexed | 2024-12-12T04:18:34Z |
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| last_indexed | 2024-12-12T04:18:34Z |
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| spelling | doaj.art-b0c6ef604f084a1d958ce3357172fc262022-12-22T00:38:23ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-05-011210.3389/fonc.2022.884559884559Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in OsteosarcomaLu Zhang0Hongxin Cao1Hongxin Cao2Guanghui Gu3Dehui Hou4Yunhao You5Xiang Li6Yunzhen Chen7Guangjun Jiao8Department of Orthopedics, Qilu Hospital of Shandong University and Spine and Spinal Cord Disease Research Center, Shandong University, Jinan, ChinaDepartment of Medical Oncology, Qilu Hospital of Shandong University, Jinan, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, ChinaDepartment of Orthopedics, Qilu Hospital of Shandong University and Spine and Spinal Cord Disease Research Center, Shandong University, Jinan, ChinaDepartment of Orthopedics, Qilu Hospital of Shandong University and Spine and Spinal Cord Disease Research Center, Shandong University, Jinan, ChinaDepartment of Orthopedics, Qilu Hospital of Shandong University and Spine and Spinal Cord Disease Research Center, Shandong University, Jinan, ChinaDepartment of Orthopedics, Qilu Hospital of Shandong University and Spine and Spinal Cord Disease Research Center, Shandong University, Jinan, ChinaDepartment of Orthopedics, Qilu Hospital of Shandong University and Spine and Spinal Cord Disease Research Center, Shandong University, Jinan, ChinaDepartment of Orthopedics, Qilu Hospital of Shandong University and Spine and Spinal Cord Disease Research Center, Shandong University, Jinan, ChinaBackgroundOsteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. microRNAs have been found to play a vital role in tumor angiogenesis. Here, we investigated the effects of miR-199a-5p on tumor growth and angiogenesis in osteosarcoma. Furthermore, the underlying molecular mechanisms and signaling pathways were explored.MethodsThe datasets were extracted from the Gene Expression Omnibus and the differentially expressed miRNAs (DEmiRNAs) were screened out by the GEO2R online platform. The potential target genes were predicted using the miRTarBase database. The predicted target genes were further analyzed by Gene Ontology and pathway enrichment analysis and a regulatory network of DEmiRNAs and their target genes was constructed. In addition, the effects of osteosarcoma cell derived exosomal miR-199a-5p on the proliferation, migration and neovascularization of HUVECs were evaluated by conducting EdU assays, Transwell experiments and tube formation assays. A dual-luciferase reporter assay was performed to detect whether VEGFA was the direct target of miR-199a-5p. Furthermore, in vivo xenograft models were established to further investigate the intrinsic role of miR-199a-5p in osteosarcoma tumorigenesis and angiogenesis.ResultsA total of 149 DE-miRNAs were screened out, including 136 upregulated miRNAs and 13 downregulated miRNAs in human osteosarcoma plasma samples compared with normal plasma samples. A total of 1313 target genes of the top three upregulated and downregulated miRNAs were predicted. In the PPI network, the top 10 hub nodes with higher degrees were identified as hub genes, such as TP53 and VEGFA. By constructing the miRNA-hub gene network, we found that most of hub genes could be potentially modulated by miR-663a, miR-199a-5p and miR-223-3p. In addition, we found that the expression level of miR-199a-5p in exosomes derived from osteosarcoma cells was remarkably higher than the osteosarcoma cells, and the exosomes derived from osteosarcoma cells were transported to HUVECs. Overexpression of miR-199a-5p could significantly inhibited HUVEC proliferation, migration and neovascularization, whereas downregulation of miR-199a-5p expression exerted the opposite effect. Moreover, the in vivo results verified that overexpression of miR-199a-5p in osteosarcoma cells could suppress the growth and angiogenesis of tumors.ConclusionOur results demonstrated that miR-199a-5p could be transported from osteosarcoma cells to HUVECs through exosomes, subsequently targeting VEGFA and inhibiting the growth and angiogenesis of osteosarcoma. Therefore, miR-199a-5p may act as a biomarker in the diagnosis and treatment of osteosarcoma.https://www.frontiersin.org/articles/10.3389/fonc.2022.884559/fullosteosarcomaexosomeangiogenesismiR-199a-5pVEGFA |
| spellingShingle | Lu Zhang Hongxin Cao Hongxin Cao Guanghui Gu Dehui Hou Yunhao You Xiang Li Yunzhen Chen Guangjun Jiao Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma Frontiers in Oncology osteosarcoma exosome angiogenesis miR-199a-5p VEGFA |
| title | Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma |
| title_full | Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma |
| title_fullStr | Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma |
| title_full_unstemmed | Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma |
| title_short | Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma |
| title_sort | exosomal mir 199a 5p inhibits tumorigenesis and angiogenesis by targeting vegfa in osteosarcoma |
| topic | osteosarcoma exosome angiogenesis miR-199a-5p VEGFA |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.884559/full |
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