{"title":"Role of S1PR1 in VEGF-exosomes mediated resistance of hepatocellular carcinoma to anti-angiogenesis therapy.","authors":"Xinghong Yao, Min Tang, Liang Li, Ye Zeng","doi":"10.1186/s12935-025-03907-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Anti-angiogenesis therapy (AAT) triggers vascular endothelial growth factor (VEGF)-exosomes secretion from tumor-associated endothelial cells (TAECs) for hepatocellular carcinoma (HCC) tubulogenesis and metastasis. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in HCC progression, but it was targeted by microRNA-9 (miR-9) that might mediate the formation of TAECs. This study aims to investigate the role of miR-9 and VEGF-exosomes in S1PR1-mediated HCC progression and resistance to AAT.</p><p><strong>Methods: </strong>The expression and distribution of miR-9 in HCC tissues were analyzed using qRT-PCR and fluorescence in situ hybridization (FISH). The impact of S1PR1 knockdown on VEGF-exosome uptake, as well as miR-9 and VEGF-exosome-induced epithelial-mesenchymal transition (EMT), migration, and invasion of HCC cells, was assessed by Transwell assays, fluorescence microscopy, and Western blotting.</p><p><strong>Results: </strong>miR-9 expression was significantly upregulated in HCC tissues and selectively localized in CD34⁺ endothelial cells within paracancerous microvessels, suggesting its role in TAEC transformation.miR-9 promoted EMT and enhanced HCC cell migration and invasion, effects that were further potentiated by VEGF-exosomes. S1PR1 knockdown significantly inhibited VEGF-exosome uptake and suppressed miR-9- and VEGF-exosome-induced EMT, migration, and invasion of HCC cells.</p><p><strong>Conclusion: </strong>In conclusion, miR-9 facilitates HCC progression by enhancing tumor malignancy and promoting AAT resistance through TAEC-mediated VEGF-exosome secretion. S1PR1 is a critical mediator of this process, and its inhibition represents a potential therapeutic strategy to overcome AAT resistance in HCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"264"},"PeriodicalIF":5.3000,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell International","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12935-025-03907-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Anti-angiogenesis therapy (AAT) triggers vascular endothelial growth factor (VEGF)-exosomes secretion from tumor-associated endothelial cells (TAECs) for hepatocellular carcinoma (HCC) tubulogenesis and metastasis. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in HCC progression, but it was targeted by microRNA-9 (miR-9) that might mediate the formation of TAECs. This study aims to investigate the role of miR-9 and VEGF-exosomes in S1PR1-mediated HCC progression and resistance to AAT.
Methods: The expression and distribution of miR-9 in HCC tissues were analyzed using qRT-PCR and fluorescence in situ hybridization (FISH). The impact of S1PR1 knockdown on VEGF-exosome uptake, as well as miR-9 and VEGF-exosome-induced epithelial-mesenchymal transition (EMT), migration, and invasion of HCC cells, was assessed by Transwell assays, fluorescence microscopy, and Western blotting.
Results: miR-9 expression was significantly upregulated in HCC tissues and selectively localized in CD34⁺ endothelial cells within paracancerous microvessels, suggesting its role in TAEC transformation.miR-9 promoted EMT and enhanced HCC cell migration and invasion, effects that were further potentiated by VEGF-exosomes. S1PR1 knockdown significantly inhibited VEGF-exosome uptake and suppressed miR-9- and VEGF-exosome-induced EMT, migration, and invasion of HCC cells.
Conclusion: In conclusion, miR-9 facilitates HCC progression by enhancing tumor malignancy and promoting AAT resistance through TAEC-mediated VEGF-exosome secretion. S1PR1 is a critical mediator of this process, and its inhibition represents a potential therapeutic strategy to overcome AAT resistance in HCC.
期刊介绍：
Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques.
The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors.
Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
