Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Dermatology, Shanxi Provincial People's Hospital, Affiliated of Shanxi Medical University, Taiyuan, China.
Basic Clin Pharmacol Toxicol. 2018 Dec;123(6):692-703. doi: 10.1111/bcpt.13090. Epub 2018 Oct 5.
Malignant melanoma is an aggressive form of cancer which is highly resistant to chemotherapy. We have previously found that gambogic acid (GA), a kind of polyprenylated xanthone, exhibits an antitumour role in melanoma. The study was designed to investigate novel mechanisms of the antitumour effect of GA in melanoma cells and implanted nude mice. Gambogic acid significantly decreased cell viability, increased apoptosis and reduced migration and invasion in A375 cells. In addition, cisplatin-induced cytotoxicity in both A375 and A375/CDDP cells was increased by GA. The expression of miR-199a-3p was increased by GA in A375 cells and implanted tumours, and inhibition of miR-199a-3p significantly prevented GA-induced effect on cell viability, apoptosis, migration, invasion and cisplatin sensitivity in A375 cells. miR-199a-3p mimics reduced tumour weight and volume in vivo and decreased cell viability, increased apoptosis and reduced migration and invasion in vitro. miR-199a-3p expression was decreased in melanoma tissues and cells, as compared with their controls. miR-199a-3p possessed a potential binding site in the 3'-UTR of zinc finger E-box binding homeobox (ZEB1). ZEB1 expression was increased in melanoma tissues and cells, as compared with their controls. ZEB1 and miR-199a-3p expression was negatively correlated in melanoma tissues. The expression of ZEB1 was decreased by GA in A375 cells and implanted tumours, and up-regulation of ZEB1 significantly prevented GA-induced effect on cell viability, apoptosis, migration, invasion and cisplatin sensitivity. Down-regulation of ZEB1 reduced tumour weight and volume in vivo and decreased cell viability, increased apoptosis and reduced migration and invasion in vitro. We identified the important roles of miR-199a-3p and ZEB1 in melanoma and elucidated the tumour suppressor function of miR-199a-3p through inhibition of ZEB1. The results highlight the importance of miR-199a-3p-ZEB1 signalling in antitumour effect of GA in malignant melanoma and provide novel targets for the chemotherapy of melanoma.
恶性黑色素瘤是一种侵袭性很强的癌症，对化疗具有高度耐药性。我们之前发现，藤黄酸（GA）是一种多聚异戊烯基查尔酮，在黑色素瘤中具有抗肿瘤作用。本研究旨在探讨 GA 在黑色素瘤细胞和植入裸鼠中的抗肿瘤作用的新机制。GA 显著降低 A375 细胞的活力，增加细胞凋亡，并减少迁移和侵袭。此外，GA 增加了顺铂诱导的 A375 和 A375/CDDP 细胞的细胞毒性。GA 增加了 A375 细胞和植入肿瘤中的 miR-199a-3p 的表达，而 miR-199a-3p 的抑制显著阻止了 GA 对 A375 细胞活力、凋亡、迁移、侵袭和顺铂敏感性的诱导作用。miR-199a-3p 模拟物减少了体内肿瘤的重量和体积，并减少了体外细胞活力、增加了细胞凋亡并减少了迁移和侵袭。与对照相比，黑色素瘤组织和细胞中的 miR-199a-3p 表达降低。miR-199a-3p 在锌指 E 框结合同源盒（ZEB1）的 3'-UTR 中具有潜在的结合位点。与对照相比，黑色素瘤组织和细胞中的 ZEB1 表达增加。黑色素瘤组织中 ZEB1 和 miR-199a-3p 的表达呈负相关。GA 降低了 A375 细胞和植入肿瘤中的 ZEB1 表达，而上调 ZEB1 显著阻止了 GA 诱导的细胞活力、凋亡、迁移、侵袭和顺铂敏感性的作用。ZEB1 的下调减少了体内肿瘤的重量和体积，并减少了体外细胞活力、增加了细胞凋亡并减少了迁移和侵袭。我们确定了 miR-199a-3p 和 ZEB1 在黑色素瘤中的重要作用，并通过抑制 ZEB1 阐明了 miR-199a-3p 的肿瘤抑制功能。结果强调了 miR-199a-3p-ZEB1 信号在 GA 抑制恶性黑色素瘤中的抗肿瘤作用中的重要性，并为黑色素瘤的化疗提供了新的靶点。
