Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin
Lymphatic metastasis is a biological procedure associated with the pathogenesis of several diseases, especially in tumor metastasis. Therefore, regulation of lymphangiogenesis has become a promising strategy for cancer therapy. In this study, we aimed to investigate the anti-lymphangiogenic effect o...
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2021-08-01
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| author | Hsien-Lin Chen Yu-Chieh Su Huang-Chi Chen Jui-Hsin Su Chang-Yi Wu Shih-Wei Wang In-Pin Lin Chung-Yi Chen Chien-Hsing Lee |
| author_facet | Hsien-Lin Chen Yu-Chieh Su Huang-Chi Chen Jui-Hsin Su Chang-Yi Wu Shih-Wei Wang In-Pin Lin Chung-Yi Chen Chien-Hsing Lee |
| author_sort | Hsien-Lin Chen |
| collection | DOAJ |
| description | Lymphatic metastasis is a biological procedure associated with the pathogenesis of several diseases, especially in tumor metastasis. Therefore, regulation of lymphangiogenesis has become a promising strategy for cancer therapy. In this study, we aimed to investigate the anti-lymphangiogenic effect of heteronemin (SP-1) isolated from the sponge <i>Hyrtios</i> sp. in vitro and in vivo. Human lymphatic endothelial cells (LECs) were utilized to evaluate the anti-lymphangiogenic effect of SP-1 in vitro. Molecular docking, western blotting, flow-cytometry, MTT and ELISA were performed to investigate the mechanism of action. For in vivo approaches, the transgenic (fli1:EGFP; gata1:DsRed) zebrafish and mouse ear sponges were used. Molecular docking studies showed that SP-1 is a potent vascular endothelial growth factor receptor 3 (VEGFR-3)-binding compound. Treatment of LEC with SP-1 reduced the phosphorylation of VEGFR-3. SP-1 suppressed the development of the thoracic duct in zebrafish and mouse lymphangiogenesis ear sponges in vivo. Mechanistically, SP-1 induced the cell cycle arrest of LECs in the G0/G1 phase and reduced the downstream of VEGFR-3, such as phosphorylated MEK/ERK and NF-κB. In addition, SP-1 inhibited LECs’ tubulogenesis and migration through the ARF-1 and MMP-9/VE-cadherin/vimentin. Overall, anti-lymphangiogenic properties of SP-1 occur by downregulating the VEGFR-3 cascade, ARF-1 and MMP-9/VE-cadherin/vimentin. Collectively, these results proposed that SP-1 might be a potential candidate for the treatment of lymphangiogenesis-associated diseases. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2021-08-01 |
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| series | Biomedicines |
| spelling | doaj-art-2b6fb40fdea14ba19464f7d38e840b432025-01-08T11:05:49ZengMDPI AGBiomedicines2227-90592021-08-0199110910.3390/biomedicines9091109Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/VimentinHsien-Lin Chen0Yu-Chieh Su1Huang-Chi Chen2Jui-Hsin Su3Chang-Yi Wu4Shih-Wei Wang5In-Pin Lin6Chung-Yi Chen7Chien-Hsing Lee8Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Liouying, Tainan 73657, TaiwanDepartment of Medicine, School of Medicine, I-Shou University, Kaohsiung 840203, TaiwanDepartment of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung 81267, TaiwanNational Museum of Marine Biology & Aquarium, Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 94401, TaiwanDepartment of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, TaiwanDepartment of Medicine, Mackay Medical College, New Taipei City 252005, TaiwanDepartment of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, TaiwanDepartment of Nutrition and Health Science, School of Medical and Health Sciences, Fooyin University, Kaohsiung 83102, TaiwanDepartment of Pharmacology, School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, TaiwanLymphatic metastasis is a biological procedure associated with the pathogenesis of several diseases, especially in tumor metastasis. Therefore, regulation of lymphangiogenesis has become a promising strategy for cancer therapy. In this study, we aimed to investigate the anti-lymphangiogenic effect of heteronemin (SP-1) isolated from the sponge <i>Hyrtios</i> sp. in vitro and in vivo. Human lymphatic endothelial cells (LECs) were utilized to evaluate the anti-lymphangiogenic effect of SP-1 in vitro. Molecular docking, western blotting, flow-cytometry, MTT and ELISA were performed to investigate the mechanism of action. For in vivo approaches, the transgenic (fli1:EGFP; gata1:DsRed) zebrafish and mouse ear sponges were used. Molecular docking studies showed that SP-1 is a potent vascular endothelial growth factor receptor 3 (VEGFR-3)-binding compound. Treatment of LEC with SP-1 reduced the phosphorylation of VEGFR-3. SP-1 suppressed the development of the thoracic duct in zebrafish and mouse lymphangiogenesis ear sponges in vivo. Mechanistically, SP-1 induced the cell cycle arrest of LECs in the G0/G1 phase and reduced the downstream of VEGFR-3, such as phosphorylated MEK/ERK and NF-κB. In addition, SP-1 inhibited LECs’ tubulogenesis and migration through the ARF-1 and MMP-9/VE-cadherin/vimentin. Overall, anti-lymphangiogenic properties of SP-1 occur by downregulating the VEGFR-3 cascade, ARF-1 and MMP-9/VE-cadherin/vimentin. Collectively, these results proposed that SP-1 might be a potential candidate for the treatment of lymphangiogenesis-associated diseases.https://www.mdpi.com/2227-9059/9/9/1109lymphangiogenesisheteroneminzebrafishARF-1MMP-9/VE-cadherin/vimentinendothelial-to-mesenchymal transition |
| spellingShingle | Hsien-Lin Chen Yu-Chieh Su Huang-Chi Chen Jui-Hsin Su Chang-Yi Wu Shih-Wei Wang In-Pin Lin Chung-Yi Chen Chien-Hsing Lee Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin Biomedicines lymphangiogenesis heteronemin zebrafish ARF-1 MMP-9/VE-cadherin/vimentin endothelial-to-mesenchymal transition |
| title | Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin |
| title_full | Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin |
| title_fullStr | Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin |
| title_full_unstemmed | Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin |
| title_short | Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin |
| title_sort | heteronemin suppresses lymphangiogenesis through arf 1 and mmp 9 ve cadherin vimentin |
| topic | lymphangiogenesis heteronemin zebrafish ARF-1 MMP-9/VE-cadherin/vimentin endothelial-to-mesenchymal transition |
| url | https://www.mdpi.com/2227-9059/9/9/1109 |
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