Mingming Deng1, Bofang Liu2, Huicong Song3, Ruoxi Yu3, Dan Zou4, Yang Chen5, Yanju Ma6, Fei Lv4, Ling Xu3, Zhe Zhang7, Qingjie Lv7, Xianghong Yang7, Xiaofang Che3, Xiujuan Qu3, Yunpeng Liu3, Ye Zhang8, Xuejun Hu9. 1. 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. 2. 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. 3. Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. 4. The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China. 5. Department of Respiratory and Infectious Disease of Geriatrics, the First Hospital of China Medical University, Shenyang 110001, China. 6. Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China. 7. Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110001, China. 8. The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China. Electronic address: yzhang21@cmu.edu.cn. 9. Department of Respiratory and Infectious Disease of Geriatrics, the First Hospital of China Medical University, Shenyang 110001, China. Electronic address: huxuejun2015@126.com.
Abstract
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.
BACKGROUND: β-Elemene is a natural agent extracted from the traditional Chinese herbal medicineCurcuma 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. HumanMMP 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.
Authors: D Jafari; M J Mousavi; S Keshavarz Shahbaz; L Jafarzadeh; S Tahmasebi; J Spoor; A Esmaeilzadeh Journal: Clin Exp Immunol Date: 2021-01-10 Impact factor: 5.732