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Article

Effects of 6,8-Diprenylgenistein on VEGF-A-Induced Lymphangiogenesis and Lymph Node Metastasis in an Oral Cancer Sentinel Lymph Node Animal Model

1
Department of Genetic Engineering and Graduate School of Biotechnology, Kyung Hee University, Yongin 446-701, Korea
2
Department of Herbal Crop Research, National Institute of Horticulture and Herbal Science, RDA, Eumseong 27709, Korea
3
Department of Horticultural Biotechnology, Kyung Hee University, Yongin 17104, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2021, 22(2), 770; https://doi.org/10.3390/ijms22020770
Received: 29 December 2020 / Revised: 10 January 2021 / Accepted: 12 January 2021 / Published: 14 January 2021
(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)
Background: The major determining factor of prognosis of oral squamous cell carcinoma is cervical lymph node metastasis. 6,8-Diprenylgenistein (6,8-DG), an isoflavonoid isolated from Cudrania tricuspidata has been reported to have anti-microbial and anti-obesity activities. However, its effects on lymphangiogenesis and lymph node metastasis in oral cancer have not yet been reported. Methods: To investigate the in vitro inhibitory effects of 6,8-DG on VEGF-A-induced lymphangiogenesis, we performed the proliferation, tube formation, and migration assay using human lymphatic microvascular endothelial cells (HLMECs). RT-PCR, Western blot, immunoprecipitation, ELISA and co-immunoprecipitation assays were used to investigate the expression levels of proteins, and mechanism of 6,8-DG. The in vivo inhibitory effects of 6,8-DG were investigated using an oral cancer sentinel lymph node (OCSLN) animal model. Results: 6,8-DG inhibited the proliferation, migration and tube formation of rhVEGF-A treated HLMECs. In addition, the in vivo lymphatic vessel formation stimulated by rhVEGF-A was significantly reduced by 6,8-DG. 6,8-DG inhibited the expression of VEGF-A rather than other lymphangiogenic factors in CoCl2-treated SCCVII cells. 6,8-DG inhibited the expression and activation of VEGFR-2 stimulated by rhVEGF-A in HLMECs. Also, 6,8-DG inhibited the activation of the lymphangiogenesis-related downstream signaling factors such as FAK, PI3K, AKT, p38, and ERK in rhVEGF-A-treated HLMECs. Additionally, 6,8-DG inhibited the expression of the hypoxia-inducible factor (HIF-1α), which is involved in the expression of VEGF-A in CoCl2-treated SCCVII cells, and 6,8-DG inhibited VEGF-A signaling via interruption of the binding of VEGF-A and VEGFR-2 in HLMECs. In the VEGF-A-induced OCSLN animal model, we confirmed that 6,8-DG suppressed tumor-induced lymphangiogenesis and SLN metastasis. Conclusion: These data suggest that 6,8-DG inhibits VEGF-A-induced lymphangiogenesis and lymph node metastasis in vitro and in vivo. Furthermore, the inhibitory effects of 6,8-DG are probably mediated by inhibition of VEGF-A expression in cancer cells and suppression of the VEGF-A/VEGFR-2 signaling pathway in HLMEC. Thus, 6,8-DG could be novel and valuable therapeutic agents for metastasis prevention and treatment of oral cancer. View Full-Text
Keywords: oral cancer; 6,8-diprenylgenistein; VEGF-A-induced lymphangiogenesis; sentinel lymph node metastasis oral cancer; 6,8-diprenylgenistein; VEGF-A-induced lymphangiogenesis; sentinel lymph node metastasis
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MDPI and ACS Style

Bae, M.G.; Hwang-Bo, J.; Lee, D.Y.; Lee, Y.-H.; Chung, I.S. Effects of 6,8-Diprenylgenistein on VEGF-A-Induced Lymphangiogenesis and Lymph Node Metastasis in an Oral Cancer Sentinel Lymph Node Animal Model. Int. J. Mol. Sci. 2021, 22, 770. https://doi.org/10.3390/ijms22020770

AMA Style

Bae MG, Hwang-Bo J, Lee DY, Lee Y-H, Chung IS. Effects of 6,8-Diprenylgenistein on VEGF-A-Induced Lymphangiogenesis and Lymph Node Metastasis in an Oral Cancer Sentinel Lymph Node Animal Model. International Journal of Molecular Sciences. 2021; 22(2):770. https://doi.org/10.3390/ijms22020770

Chicago/Turabian Style

Bae, Mun G., Jeon Hwang-Bo, Dae Y. Lee, Youn-Hyung Lee, and In S. Chung 2021. "Effects of 6,8-Diprenylgenistein on VEGF-A-Induced Lymphangiogenesis and Lymph Node Metastasis in an Oral Cancer Sentinel Lymph Node Animal Model" International Journal of Molecular Sciences 22, no. 2: 770. https://doi.org/10.3390/ijms22020770

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