Homoharringtonine inhibits the progression of hepatocellular carcinoma by suppressing the PI3K/AKT/GSK3β/Slug signaling pathway
Homoharringtonine inhibits the progression of hepatocellular carcinoma by suppressing the PI3K/AKT/GSK3β/Slug signaling pathway
复制标题
高三尖杉酯碱通过抑制 PI3K/AKT/GSK3 beta/Slug 信号通路抑制肝细胞癌的进展
DOI：
10.4149/neo_2021_210113n57
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发表时间：
2021-01-01
期刊：
影响因子：
3
通讯作者：
Yang, Xiu-Hua
中科院分区：
文献类型：
--
作者：
Liu, Hong-Yuan;Dong, Tian-Xiu;Yang, Xiu-Hua
高三尖杉酯碱（Homoharringtonine，HHT）是首次从南方红豆杉Cetylaxus harringtonia（Knight ex J.福布斯）K. Koch和南方红豆杉（Ceutaxus fortunei Hook）。树皮提取物用于治疗白血病，近年来也被用于中医药（TCM）治疗实体瘤。然而，HHT在肝细胞癌（HCC）发展过程中的抑制机制研究很少。我们的目的是评估HHT在体外和体内对肝癌的抗肿瘤效果，并阐明其潜在的分子机制。HHT对肝癌细胞系HCCLM 3、HepG 2和Huh 7的体外抗肿瘤作用进行了评价。MTT法和集落形成实验检测细胞毒性和增殖能力。用流式细胞仪检测HHT处理的肝癌细胞的细胞周期进程和凋亡。为了确定HCC细胞的迁移和侵袭能力，使用伤口愈合和Transwell测定。最后，使用western blot分析来揭示所涉及的蛋白质。我们还建立了一种异种移植裸鼠模型，用于体内评估HHT的临床前疗效，主要使用苏木精和伊红染色，免疫组织化学，超声成像（USI）和磁共振成像（MRI）。HHT可抑制肝癌细胞的增殖、迁移、侵袭和上皮-间质转化（EMT），并诱导细胞周期阻滞于G2期和凋亡。在肝癌移植瘤模型中，HHT显示出明显的抑瘤作用。令人惊讶的是，HHT通过PI 3 K/AKT/GSK 3 β信号传导途径也降低了Slug表达，至少部分抑制了HCC通过PI 3 K/AKT/GSK 3 β/Slug信号传导途径的生长。
Homoharringtonine (HHT), was first isolated from the bark of Cephalotaxus harringtonia (Knight ex J. Forbes) K. Koch and Cephalotaxus fortunei Hook trees. The bark extract is used to treat leukemia and in recent years has also been used in traditional Chinese medicine (TCM) to treat solid tumors. However, the inhibitory mechanism of HHT in the progression of hepatocellular carcinoma (HCC) is rarely studied. We aimed to evaluate the antitumor efficacy of HHT on HCC in vitro and in vivo and elucidate the underlying molecular mechanism(s). HCC cell lines, including HCCLM3, HepG2, and Huh7, were used to evaluate the antitumor efficacy of HHT in vitro. Cytotoxicity and proliferative ability were evaluated by MTT and colony formation assays. Cell cycle progression and apoptosis in HHT-treated HCC cells were evaluated by flow cytometry. To determine the migration and invasion abilities of HCC cells, wound-healing and Transwell assays were used. Finally, western blot analysis was used to reveal the proteins involved. We also established a xenograft nude mouse model for in vivo assessments of the preclinical efficacy of HHT, mainly using hematoxylin and eosin staining, immunohistochemistry, ultrasound imaging (USI), and magnetic resonance imaging (MRI). HHT suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, and induced cell cycle arrest at the G2 phase and apoptosis. In the HCC xenograft model, HHT showed an obvious tumor-suppressive effect. Surprisingly, Slug expression was also decreased by HHT via the PI3K/AKT/GSK3 beta signaling pathway at least partially suppressed the growth of HCC via the PI3K/AKT/GSK3 beta/Slug signaling pathway.