Effects of arsenic trioxide on migration, invasion and apoptosis of hepatocellular carcinoma HepG2 cells_Journal of Biomedical Engineering

Authors：

HE Jia ¹ , XU Bowen ¹ , GAO Wenbo ¹ , SU Guanyue ¹ , YU Hongchi ² , SHEN Yang ¹ ,  LIU Xiaoheng ¹

1. Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, P.R.China;
2. National Engineering Research Center for Biomaterials, Chengdu 610065, P.R China;

Corresponding author：

LIU Xiaoheng, Email: liuxiaohg@scu.edu.cn

Keywords：

arsenic trioxide; HepG2 cells; migration; invasion; apoptosis

DOI：

10.7507/1001-5515.201907044

Video：

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The article aims to explore the optimal concentration of arsenic trioxide (As₂O₃) on HepG2 of liver cancer cells, and the effect of As₂O₃ on the migration, invasion and apoptosis of HepG2 cells. In this study, the activity of HepG2 cells treated with 0, 1, 2, 4, 8, 16, 32 μmol/L As₂O₃ was tested by CCK-8 method, the semi-inhibitory concentration (IC50) was calculated, and the morphological changes of HepG2 cells were observed after the action of As₂O₃ at IC50 concentration for 12, 24, 48 h. The effect of As₂O₃ on cell migration and invasion ability was verified by wound healing experiment and Transwell invasion experiment. Western blot and qRT-PCR were used to detect the effects of As₂O₃ on the gene and protein expression levels related to cell migration, invasion and apoptosis. The results showed that, compared with the control group, the activity of HepG2 cells decreased with the increase of the concentration of As₂O₃ treatment, showing a dose-dependent effect, and its IC50 was 7.3 μmol/L. After 24 hours’ treatment with 8 μmol/L As₂O₃, HepG2 cells underwent significant apoptosis, and its migration and invasion abilities were significantly reduced. In addition, the protein expression levels of RhoA, Cdc42, Rac1 and matrix metalloproteinase-9 (MMP-9) were down-regulated, the protein and mRNA expression levels of anti-apoptotic gene Bcl-2 were significantly down-regulated, and the protein and mRNA expression levels of pro-apoptotic genes Bax and Caspase-3 were significantly up-regulated. The above results indicate that certain concentration of As₂O₃ can inhibit the migration and invasion of hepatocellular carcinoma cells and promote the apoptosis of hepatocellular carcinoma cells.

Citation： HE Jia, XU Bowen, GAO Wenbo, SU Guanyue, YU Hongchi, SHEN Yang, LIU Xiaoheng. Effects of arsenic trioxide on migration, invasion and apoptosis of hepatocellular carcinoma HepG2 cells. Journal of Biomedical Engineering, 2020, 37(1): 105-111. doi: 10.7507/1001-5515.201907044 Copy

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8.	Nguyen A T, Chia J, Ros M, et al. Organelle specific O-glycosylation drives MMP14 activation, tumor growth, and metastasis. Cancer Cell, 2017, 32(5): 639-653.
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14.	Wang H, Liu Y, Wang X, et al. Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma. Cancer, 2015, 121(17): 2917-2925.
15.	Yang M H, Chang K J, Li B, et al. Arsenic trioxide suppresses tumor growth through antiangiogenesis via Notch signaling blockade in small-cell lung cancer. Biomed Res Int, 2019, 2019: 4647252.
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17.	Hoffman E A, Gizelska K, Mirowski M, et al. Arsenic trioxide downregulates cancer procoagulant activity in MCF-7 and WM-115 cell lines in vitro. Contemp Oncol (Pozn), 2015, 19(2): 108-112.
18.	Wang Y, Jiang F, Jiao K, et al. De-methylation of miR-148a by arsenic trioxide enhances sensitivity to chemotherapy via inhibiting the NF-κB pathway and CSC like properties. Exp Cell Res, 2020, 386(2): 111739.
19.	Song J, Zhao Z, Fan X, et al. Shikonin potentiates the effect of arsenic trioxide against human hepatocellular carcinoma in vitro and in vivo. Oncotarget, 2016, 7(43): 70504-70515.
20.	Huang Z, Zhou J K, Wang K, et al. PDLIM1 inhibits tumor metastasis through activating Hippo signaling in hepatocellular carcinoma. Hepatology, 2019. DOI: 10.1002/hep.30930.
21.	Ma M, Xu H, Liu G, et al. MITA1, a novel energy stress-inducible lncRNA, promotes hepatocellular carcinoma metastasis. Hepatology, 2019, 10: 1002.
22.	Khairul I, Wang Q Q, Jiang Y H, et al. Metabolism, toxicity and anticancer activities of arsenic compounds. Oncotarget, 2017, 8(14): 23905-23926.
23.	Lu W, Yang C, Du P, et al. Effects of arsenic trioxide on the expression of ezrin in hepatocellular carcinoma. Medicine (Baltimore), 2017, 96(35): e7602.
24.	Zheng H, Fu Y, Yang T. Propofol inhibits proliferation, migration, and invasion of hepatocellular carcinoma cells by downregulating Twist. J Cell Biochem, 2019, 120(8): 12803-12809.
25.	Zhang C, Yu Y, Huang Q, et al. SIRT6 regulates the proliferation and apoptosis of hepatocellular carcinoma via the ERK1/2 signaling pathway. Mol Med Rep, 2019, 20(2): 1575-1582.

1. Craig A J, von Felden J, Garcia-Lezana T, et al. Tumour evolution in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2019. DOI: 10.1038/s41575-019-0229-4.
2. Rao S, Mishra L. Targeting TGF-β signaling in liver cancer. Hepatology, 2019, 69(4): 1375-1378.
3. Chen W, Zheng R, Baade P D, et al. Cancer statistics in China. Ca Cancer J Clin, 2016, 66(2): 115-132.
4. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin, 2018, 68(6): 394-424.
5. Wang C, Vegna S, Jin H, et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature, 2019, 574(7777): 268-272.
6. Milette S, Hashimoto M, Perrino S, et al. Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases. Nat Commun, 2019, 10(1): 5745.
7. Ye Q H, Zhu W W, Zhang J B, et al. GOLM1 modulates EGFR/RTK cell-surface recycling to drive hepatocellular carcinoma metastasis. Cancer Cell, 2016, 30(3): 444-458.
8. Nguyen A T, Chia J, Ros M, et al. Organelle specific O-glycosylation drives MMP14 activation, tumor growth, and metastasis. Cancer Cell, 2017, 32(5): 639-653.
9. Koppisetti R K, Fulcher Y G, Jurkevich A, et al. Ambidextrous binding of cell and membrane bilayers by soluble matrix metalloproteinase-12. Nat Commun, 2014, 5: 5552.
10. Castleberry S A, Almquist B D, Li W, et al. Self-assembled wound dressings silence MMP-9 and improve diabetic wound healing in vivo. Adv Mater Weinheim, 2016, 28(9): 1809-1817.
11. Jansen S, Gosens R, Wieland T, et al. Paving the Rho in cancer metastasis: Rho GTPases and beyond. Pharmacol Ther, 2017, 183: 1-21.
12. Agarwal P, Zaidel-Bar R. Principles of actomyosin regulation in vivo. Trends Cell Biol, 2019, 29(2): 150-163.
13. Baugher P J, Krishnamoorthy L, Price J E, et al. Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Breast Cancer Res, 2005, 7(6): R965-R974.
14. Wang H, Liu Y, Wang X, et al. Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma. Cancer, 2015, 121(17): 2917-2925.
15. Yang M H, Chang K J, Li B, et al. Arsenic trioxide suppresses tumor growth through antiangiogenesis via Notch signaling blockade in small-cell lung cancer. Biomed Res Int, 2019, 2019: 4647252.
16. Zhong L, Xu F, Chen F. Arsenic trioxide induces the apoptosis and decreases NF-κB expression in lymphoma cell lines. Oncol Lett, 2018, 16(5): 6267-6274.
17. Hoffman E A, Gizelska K, Mirowski M, et al. Arsenic trioxide downregulates cancer procoagulant activity in MCF-7 and WM-115 cell lines in vitro. Contemp Oncol (Pozn), 2015, 19(2): 108-112.
18. Wang Y, Jiang F, Jiao K, et al. De-methylation of miR-148a by arsenic trioxide enhances sensitivity to chemotherapy via inhibiting the NF-κB pathway and CSC like properties. Exp Cell Res, 2020, 386(2): 111739.
19. Song J, Zhao Z, Fan X, et al. Shikonin potentiates the effect of arsenic trioxide against human hepatocellular carcinoma in vitro and in vivo. Oncotarget, 2016, 7(43): 70504-70515.
20. Huang Z, Zhou J K, Wang K, et al. PDLIM1 inhibits tumor metastasis through activating Hippo signaling in hepatocellular carcinoma. Hepatology, 2019. DOI: 10.1002/hep.30930.
21. Ma M, Xu H, Liu G, et al. MITA1, a novel energy stress-inducible lncRNA, promotes hepatocellular carcinoma metastasis. Hepatology, 2019, 10: 1002.
22. Khairul I, Wang Q Q, Jiang Y H, et al. Metabolism, toxicity and anticancer activities of arsenic compounds. Oncotarget, 2017, 8(14): 23905-23926.
23. Lu W, Yang C, Du P, et al. Effects of arsenic trioxide on the expression of ezrin in hepatocellular carcinoma. Medicine (Baltimore), 2017, 96(35): e7602.
24. Zheng H, Fu Y, Yang T. Propofol inhibits proliferation, migration, and invasion of hepatocellular carcinoma cells by downregulating Twist. J Cell Biochem, 2019, 120(8): 12803-12809.
25. Zhang C, Yu Y, Huang Q, et al. SIRT6 regulates the proliferation and apoptosis of hepatocellular carcinoma via the ERK1/2 signaling pathway. Mol Med Rep, 2019, 20(2): 1575-1582.

Journal of Biomedical Engineering

Effects of arsenic trioxide on migration, invasion and apoptosis of hepatocellular carcinoma HepG2 cells

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