S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression
Abstract Angiogenesis is a fundamental process underlying the occurrence, growth and metastasis of hepatocellular carcinoma (HCC), a prevalent tumour type with an extremely poor prognosis due to abundant vasculature. However, the underlying mechanism of angiogenesis in HCC remains largely unknown. H...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05210-z |
| _version_ | 1798002967640539136 |
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| author | Xuehong Wang Zhidong Qiu Wei Dong Zebin Yang Junnan Wang Hailiang Xu Tian Sun Zhaoquan Huang Junfei Jin |
| author_facet | Xuehong Wang Zhidong Qiu Wei Dong Zebin Yang Junnan Wang Hailiang Xu Tian Sun Zhaoquan Huang Junfei Jin |
| author_sort | Xuehong Wang |
| collection | DOAJ |
| description | Abstract Angiogenesis is a fundamental process underlying the occurrence, growth and metastasis of hepatocellular carcinoma (HCC), a prevalent tumour type with an extremely poor prognosis due to abundant vasculature. However, the underlying mechanism of angiogenesis in HCC remains largely unknown. Herein, we found that sphingosine-1-phosphate receptor 1 (S1PR1) plays an important role in HCC angiogenesis. S1PR1 was found to be selectively and highly expressed in the blood vessels of HCC tissues compared with those of paratumour tissues. Functionally, high expression of S1PR1 in endothelial cells (ECs) promoted angiogenesis and progression of HCC in vitro and in vivo. Mechanistically, proangiogenic factors (S1P, IL-6, VEGFA) in conditioned medium from HCC cells induced the upregulation of S1PR1 in ECs via the phosphorylation of STAT3 at Y705. Further study also revealed that S1PR1 promotes angiogenesis by decreasing ceramide levels via CerS3 downregulation. Interestingly, we demonstrated that S1PR1 downregulates CerS3 by inducing CerS6 translocation into the nucleus to inhibit CerS3 at the transcriptional level in ECs. In addition, we found that a high concentration of Lenvatinib significantly downregulated the expression of S1PR1 and obviously enhanced S1PR1 knockdown-mediated angiogenesis inhibition, indicating that S1PR1 may be a target by which Lenvatinib combats angiogenesis in HCC. Thus, S1PR1 may be an important target for suppressing angiogenesis in HCC, and inhibiting S1PR1 is a promising approach to antitumor therapy in HCC. |
| first_indexed | 2024-04-11T12:00:46Z |
| format | Article |
| id | doaj.art-4d52d8f880a04b63b75b4c35ca6e0f7b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T12:00:46Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-4d52d8f880a04b63b75b4c35ca6e0f7b2022-12-22T04:24:51ZengNature Publishing GroupCell Death and Disease2041-48892022-09-0113911510.1038/s41419-022-05210-zS1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progressionXuehong Wang0Zhidong Qiu1Wei Dong2Zebin Yang3Junnan Wang4Hailiang Xu5Tian Sun6Zhaoquan Huang7Junfei Jin8Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityGuangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityGuangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityGuangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityGuangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityGuangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityGuangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityDepartment of Pathology, the First Affiliated Hospital of Guangxi Medical UniversityGuangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical UniversityAbstract Angiogenesis is a fundamental process underlying the occurrence, growth and metastasis of hepatocellular carcinoma (HCC), a prevalent tumour type with an extremely poor prognosis due to abundant vasculature. However, the underlying mechanism of angiogenesis in HCC remains largely unknown. Herein, we found that sphingosine-1-phosphate receptor 1 (S1PR1) plays an important role in HCC angiogenesis. S1PR1 was found to be selectively and highly expressed in the blood vessels of HCC tissues compared with those of paratumour tissues. Functionally, high expression of S1PR1 in endothelial cells (ECs) promoted angiogenesis and progression of HCC in vitro and in vivo. Mechanistically, proangiogenic factors (S1P, IL-6, VEGFA) in conditioned medium from HCC cells induced the upregulation of S1PR1 in ECs via the phosphorylation of STAT3 at Y705. Further study also revealed that S1PR1 promotes angiogenesis by decreasing ceramide levels via CerS3 downregulation. Interestingly, we demonstrated that S1PR1 downregulates CerS3 by inducing CerS6 translocation into the nucleus to inhibit CerS3 at the transcriptional level in ECs. In addition, we found that a high concentration of Lenvatinib significantly downregulated the expression of S1PR1 and obviously enhanced S1PR1 knockdown-mediated angiogenesis inhibition, indicating that S1PR1 may be a target by which Lenvatinib combats angiogenesis in HCC. Thus, S1PR1 may be an important target for suppressing angiogenesis in HCC, and inhibiting S1PR1 is a promising approach to antitumor therapy in HCC.https://doi.org/10.1038/s41419-022-05210-z |
| spellingShingle | Xuehong Wang Zhidong Qiu Wei Dong Zebin Yang Junnan Wang Hailiang Xu Tian Sun Zhaoquan Huang Junfei Jin S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression Cell Death and Disease |
| title | S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression |
| title_full | S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression |
| title_fullStr | S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression |
| title_full_unstemmed | S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression |
| title_short | S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression |
| title_sort | s1pr1 induces metabolic reprogramming of ceramide in vascular endothelial cells affecting hepatocellular carcinoma angiogenesis and progression |
| url | https://doi.org/10.1038/s41419-022-05210-z |
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