Li Zhaoxiang, Zhang Qi, Zhang Xinyuan, Jin Quanxin, Yue Qi, Li Na, Liu Huan, Fujimoto Manabu, Jin Guihua
Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji, China.
Department of Dermatology, Graduate School of Medicine, Osaka University, Laboratory of Cutaneous Immunology, Osaka UniversityImmunology Frontier Research Center, Osaka, Japan.
Phytother Res. 2025 Apr;39(4):1679-1693. doi: 10.1002/ptr.8065. Epub 2023 Nov 19.
Tumor angiogenesis is critical for tumor metastasis by providing oxygen, nutrients, and metastatic pathways. As a potential anti-angiogenic agent, Dihydroartemisinin (DHA) can effectively inhibit tumor metastasis. However, the mechanism how it regulates angiogenesis to affect tumor metastasis has not been fully clarified. To investigate the mechanisms of how DHA regulates melanoma progression. In this study, bioinformatics methods were used to analyze the correlation between angiogenesis and melanoma metastasis. Then, B16F10, A375, HUVECs and mouse metastasis models were adapted to clarify the inhibition of DHA in melanoma. GESA analysis revealed melanoma metastasis significantly positive correlated with angiogenesis. Meanwhile, DHA significantly decreased melanoma nodules and lung wet weight in metastatic tumor mice, and inhibited the expression of the angiogenic marker CD31 in vitro and in vivo. Similarly, DHA inhibited the expression of the angiogenic signal molecule VEGFR2 in A375 and B16F10 cells, and significantly suppressed the formation of their tubular structures. DHA-treated supernatants significantly inhibited the tubule-forming ability as well as lateral and longitudinal migration ability of HUVECs compared with untreated melanoma cell supernatants. Screening yielded the angiogenic pathways HIF-1α/VEGF, PI3K/ATK/mTOR associated with melanoma metastasis, and DHA may inhibit tumor metastasis by inhibiting these angiogenic pathways in melanoma cells to inhibit tumor metastasis. Further non-targeted metabolomics analysis revealed that DHA-treated model mice produced differential metabolites that were also associated with angiogenic pathways. DHA inhibits melanoma invasion and metastasis by mediating angiogenesis. These results have important implications for the potential use of DHA in treatment of melanoma.
肿瘤血管生成通过提供氧气、营养物质和转移途径，对肿瘤转移至关重要。双氢青蒿素（DHA）作为一种潜在的抗血管生成剂，可有效抑制肿瘤转移。然而，其调节血管生成以影响肿瘤转移的机制尚未完全阐明。为了研究DHA调节黑色素瘤进展的机制。在本研究中，采用生物信息学方法分析血管生成与黑色素瘤转移之间的相关性。然后，利用B16F10、A375、人脐静脉内皮细胞（HUVECs）和小鼠转移模型来阐明DHA对黑色素瘤的抑制作用。基因集富集分析（GESA）显示黑色素瘤转移与血管生成显著正相关。同时，DHA显著减少了转移性肿瘤小鼠的黑色素瘤结节和肺湿重，并在体外和体内抑制血管生成标志物CD31的表达。同样，DHA抑制A375和B16F10细胞中血管生成信号分子VEGFR2的表达，并显著抑制其管状结构的形成。与未处理的黑色素瘤细胞上清液相比，DHA处理的上清液显著抑制HUVECs的小管形成能力以及横向和纵向迁移能力。筛选出与黑色素瘤转移相关的血管生成途径HIF-1α/VEGF、PI3K/ATK/mTOR，DHA可能通过抑制黑色素瘤细胞中的这些血管生成途径来抑制肿瘤转移。进一步的非靶向代谢组学分析表明，DHA处理的模型小鼠产生了也与血管生成途径相关的差异代谢物。DHA通过介导血管生成抑制黑色素瘤的侵袭和转移。这些结果对DHA在黑色素瘤治疗中的潜在应用具有重要意义。
