Abstract | BACKGROUND: 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.
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Authors | Mun Gyeong Bae, Jeon Hwang-Bo, Dae Young Lee, Youn-Hyung Lee, In Sik Chung |
Journal | International journal of molecular sciences
(Int J Mol Sci)
Vol. 22
Issue 2
(Jan 14 2021)
ISSN: 1422-0067 [Electronic] Switzerland |
PMID | 33466636
(Publication Type: Journal Article)
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Chemical References |
- 6,8-diprenylgenistein
- Anticarcinogenic Agents
- Vascular Endothelial Growth Factor A
- Genistein
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Topics |
- Animals
- Anticarcinogenic Agents
(pharmacology, therapeutic use)
- Cell Line
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Female
- Genistein
(analogs & derivatives, pharmacology, therapeutic use)
- Humans
- Lymphangiogenesis
(drug effects)
- Lymphatic Metastasis
(drug therapy, pathology)
- Mice
- Mice, Inbred BALB C
- Mouth Neoplasms
(drug therapy, metabolism, pathology)
- Sentinel Lymph Node
(drug effects, metabolism, pathology)
- Vascular Endothelial Growth Factor A
(metabolism)
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