β-榄香烯通过 miR-1323/Cbl-b/EGFR 通路抑制多药耐药胃癌细胞的转移。
β-Elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through miR-1323/Cbl-b/EGFR pathway.
机构信息
Department of Respiratory and Infectious Disease of Geriatrics, the First Hospital of China Medical University, Shenyang 110001, China; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100005, China.
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, China.
出版信息
Phytomedicine. 2020 Apr;69:153184. doi: 10.1016/j.phymed.2020.153184. Epub 2020 Feb 10.
BACKGROUND
β-Elemene is a natural agent extracted from the traditional Chinese herbal medicine Curcuma wenyujin that is a promising novel plant-derived drug with broad-spectrum anticancer activity. Our previous study identified an enhanced capacity for metastasis in multidrug resistant (MDR) gastric cancer and breast cancer cells. However, the anti-metastatic effects of β-Elemene on MDR cancer cells remain unknown.
PURPOSE
In this study, we posit the hypothesis that β-elemene possesses antimetastatic effects on MDR cancer cells.
METHODS
Cell viability assay was used to assess the resistance of SGC7901/ADR cells and the cytotoxic effects of β-Elemene. Wound healing, transwell assay and lung metastatic mice model were used to the anti-metastasis effects of β-Elemene. MicroRNA microarray analysis was used to explore potential regulated miRNAs. Luciferase reporter assay was used to identify the direct target. Human MMP antibody array, western blot, immunoprecipitation, qRT-PCR analyses and immunohistochemistry were conducted to investigate the underlying anti-metastasis mechanism of β-Elemene.
RESULTS
In this study, we found that β-Elemene significantly inhibited the metastatic capacity of MDR gastric cells in vivo and in vitro. Mechanistically, we found that β-Elemene regulated MMP-2/9 expression and reversed epithelial-mesenchymal transition. Further studies showed that β-Elemene upregulated Cbl-b expression, resulting in inhibition of the EGFR-ERK/AKT pathways, which regulate MMP-2/9. Additionally, we confirmed that β-Elemene upregulated Cbl-b by inhibiting miR-1323 expression. Finally, we found that numbers of metastatic tumor nodules were significantly decreased in the lungs of nude mice after β-Elemene treatment.
CONCLUSION
Our results suggested that β-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis.
背景
β-榄香烯是从莪术等传统中药中提取的天然药物，是一种具有广谱抗癌活性的新型植物来源药物。我们之前的研究发现，多药耐药（MDR）胃癌和乳腺癌细胞的转移能力增强。然而，β-榄香烯对 MDR 癌细胞的抗转移作用尚不清楚。
目的
在本研究中，我们假设β-榄香烯对 MDR 癌细胞具有抗转移作用。
方法
采用细胞活力测定法评估 SGC7901/ADR 细胞的耐药性和β-榄香烯的细胞毒性。划痕愈合实验、Transwell 实验和肺转移小鼠模型用于评估β-榄香烯的抗转移作用。miRNA 微阵列分析用于探索潜在的调节 miRNA。荧光素酶报告基因实验用于鉴定直接靶点。采用人 MMP 抗体阵列、western blot、免疫沉淀、qRT-PCR 分析和免疫组化分析研究β-榄香烯的抗转移作用机制。
结果
本研究发现β-榄香烯显著抑制 MDR 胃癌细胞在体内和体外的转移能力。机制上，我们发现β-榄香烯调节 MMP-2/9 表达并逆转上皮-间充质转化。进一步的研究表明，β-榄香烯上调 Cbl-b 表达，从而抑制 EGFR-ERK/AKT 通路，调节 MMP-2/9。此外，我们证实β-榄香烯通过抑制 miR-1323 表达而上调 Cbl-b。最后，我们发现β-榄香烯治疗后裸鼠肺部转移瘤结节数量明显减少。
结论
我们的研究结果表明，β-榄香烯通过调节 miR-1323/Cbl-b/EGFR 信号通路抑制 MDR 胃癌细胞的转移。
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