切换至 "中华医学电子期刊资源库"

中华肝脏外科手术学电子杂志 ›› 2016, Vol. 05 ›› Issue (02) : 114 -118. doi: 10.3877/cma.j.issn.2095-3232.2016.02.012

所属专题: 文献

基础研究

三氧化二砷逆转低浓度索拉非尼对人肝癌细胞促迁移作用及其机制
陈洁盈1, 陈耀庭2, 林泽宇1, 吴祥1, 曾柏强3, 张红卫3,()   
  1. 1. 510120 广州,广东省恶性肿瘤基因调控和靶向治疗重点实验室;中山大学孙逸仙纪念医院肝胆外科
    2. 中山大学孙逸仙纪念医院放射介入科
    3. 中山大学孙逸仙纪念医院肝胆外科
  • 收稿日期:2016-01-11 出版日期:2016-04-10
  • 通信作者: 张红卫
  • 基金资助:
    广东省科技计划项目(2012B031800073)

Inhibitory effect and mechanism of arsenic trioxide on human hepatocellular carcinoma cells migration induced by low dose of sorafenib

Jieying Chen1, Yaoting Chen2, Zeyu Lin1, Xiang Wu1, Baiqiang Zeng3, Hongwei Zhang3,()   

  1. 1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
    2. Department of Radiologic Intervention, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
    3. Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
  • Received:2016-01-11 Published:2016-04-10
  • Corresponding author: Hongwei Zhang
  • About author:
    Corresponding author: Zhang Hongwei, Email:
引用本文:

陈洁盈, 陈耀庭, 林泽宇, 吴祥, 曾柏强, 张红卫. 三氧化二砷逆转低浓度索拉非尼对人肝癌细胞促迁移作用及其机制[J/OL]. 中华肝脏外科手术学电子杂志, 2016, 05(02): 114-118.

Jieying Chen, Yaoting Chen, Zeyu Lin, Xiang Wu, Baiqiang Zeng, Hongwei Zhang. Inhibitory effect and mechanism of arsenic trioxide on human hepatocellular carcinoma cells migration induced by low dose of sorafenib[J/OL]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2016, 05(02): 114-118.

目的

探讨三氧化二砷逆转低浓度索拉非尼对人肝癌细胞促进迁移作用及其机制。

方法

取对数生长期的人肝癌细胞MHCC97H,分别以三氧化二砷2 μmol/L(三氧化二砷组)、索拉非尼3 μmol/L(索拉非尼组)、两者联合(联合组)、LY294002 50 μmol/L(LY组)及索拉非尼3 μmol/L + LY294002 50 μmol/L(LY+索拉非尼组)作用于细胞,并以仅含二甲基亚砜(DMSO)作为对照组。细胞划痕实验和Transwell迁移实验分别检测细胞横向和纵向迁移能力。Western blot实验检测p-Akt、E-cadherin、Vimentin、Snail蛋白表达。实验数据比较采用单因素方差分析和Bonferroni法。

结果

细胞划痕实验检测索拉非尼、三氧化二砷、联合组细胞横向迁移速率分别为对照组的(1.59±0.14)、(0.39±0.08)、(0.58±0.12)倍(t=7.20,-12.58,-6.62;P<0.05)。Transwell迁移实验检测索拉非尼、三氧化二砷、联合组及对照组细胞数分别为(285±26)、(169±18)、(194±19)、(228±9)个。与对照组相比,索拉非尼组细胞数明显增多(t=3.48,P<0.05),三氧化二砷组明显减少(t=-3.80,P<0.05),且联合组较索拉非尼组明显减少(t=-5.67,P<0.05)。Western blot检测显示,与对照组比,索拉非尼组p-Akt、Snail、Vimentin的表达增强,E-cadherin的表达减弱。三氧化二砷、联合组、LY组及LY+索拉非尼组p-Akt、Snail、Vimentin的表达减弱,E-cadherin的表达增强。

结论

三氧化二砷可通过抑制PI3K/Akt/Snail通路的激活,阻止人肝癌细胞上皮间质化,逆转低浓度索拉非尼对人肝癌细胞促迁移作用。

Objective

To investigate the inhibitory effect and mechanism of arsenic trioxide on hepatocellular carcinoma (HCC) cells migration induced by low dose of sorafenib.

Methods

Human HCC cells MHCC97H in logarithmic phase were treated with 2 μmol/L arsenic trioxide (arsenic trioxide group), 3 μmol/L sorafenib (sorafenib group), 2 μmol/L arsenic trioxide + 3 μmol/L sorafenib (combination group), 50 μmol/L LY294002(LY group) and 3 μmol/L sorafenib + 50 μmol/L LY294002 (LY+ sorafenib group) respectively. Dimethyl sulfoxide (DMSO) was used in the control group. Wound healing assay and Transwell migration assay were used to detect the ability of horizontal and vertical cell migration. The expression of p-Akt, E-cadherin, Vimentin and Snail proteins was measured by Western blot. The experiment data were compared using one-way ANOVA and Bonferroni test.

Results

Wound healing assay revealed that the horizontal migration speed in the sorafenib, arsenic trioxide and combination groups was (1.59±0.14), (0.39±0.08) and (0.58±0.12) times of that in the control group (t=7.20, -12.58, -6.62; P<0.05). Transwell migration assay revealed that the number of cells in the sorafenib, arsenic trioxide, combination and control groups was 285±26, 169±18, 194±19 and 228±9 respectively. Compared with the control group, the number of cells was significantly increased in the sorafenib group (t=3.48, P<0.05), whereas significantly decreased in the arsenic trioxide group (t=-3.80, P<0.05). The number of cells in the combination group was significantly decreased than that in the sorafenib group (t=-5.67, P<0.05). Western blot revealed that the expression of p-Akt, Snail and Vimentin proteins was up-regulated, whereas the expression of E-cadherin protein was down-regulated in the sorafenib group compared with those in the control group. Compared with the control group, the expression of p-Akt, Snail and Vimentin proteins was down-regulated whereas the expression of E-cadherin protein was up-regulated in the arsenic trioxide, combination, LY and LY + sorafenib groups.

Conclusion

Arsenic trioxide can inhibit the epithelial-mesenchymal transition and reverse the promoting effect of low-dose sorafenib upon MHCC97H cell migration through suppressing the activation of PI3K/Akt/Snail signaling pathway.

图1 四组细胞迁移能力Transwell实验
[1]
Kang TW, Rhim H. Recent advances in tumor ablation for hepatocellular carcinoma[J]. Liver Cancer, 2015, 4(3): 176-187.
[2]
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008, 359(4): 378-390.
[3]
Ch'Ang HJ. Optimal combination of antiangiogenic therapy for hepatocellular carcinoma[J]. World J Hepatol, 2015, 7(16): 2029-2040.
[4]
孙炜,宋祥和,卞勇华,等.索拉菲尼联合紫杉醇对HepG2细胞的抑制作用及其对cyclinD1表达水平的影响[J].中国老年学杂志,2015(2): 438-440.
[5]
Jung DH, Hwang S, Song GW, et al. An interim safety analysis of hepatocellular carcinoma patients administrating oral vitamin K with or without sorafenib[J]. Korean J Hepatobiliary Pancreat Surg, 2015, 19(1): 1-5.
[6]
Liu N, Tai S, Ding B, et al. Arsenic trioxide synergizes with everolimus (Rad001) to induce cytotoxicity of ovarian cancer cells through increased autophagy and apoptosis[J]. Endocr Relat Cancer, 2012, 19(5): 711-723.
[7]
Gao YH, Zhang HP, Yang SM, et al. Inactivation of Akt by arsenic trioxide induces cell death via mitochondrial-mediated apoptotic signaling in SGC-7901 human gastric cancer cells[J]. Oncol Rep, 2014, 31(4): 1645-1652.
[8]
Cai X, Yu K, Zhang L, et al. Synergistic inhibition of colon carcinoma cell growth by Hedgehog-Gli1 inhibitor arsenic trioxide and phosphoinositide 3-kinase inhibitor LY294002[J]. Onco Targets Ther, 2015(8): 877-883.
[9]
孟艳莉,胡鸿涛,黎海亮,等.三氧化二砷联合动脉化疗栓塞治疗原发性肝癌肺转移的临床疗效观察[J].中华内科杂志,2012, 51(12): 971-974.
[10]
Zhang KZ, Zhang QB, Zhang QB, et al. Arsenic trioxide induces differentiation of CD133 + hepatocellular carcinoma cells and prolongs posthepatectomy survival by targeting GLI1 expression in a mouse model[J]. J Hematol Oncol, 2014(7): 28.
[11]
Lu L, Sun HC, Zhang W, et al. Aspirin minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating HTATIP2 in hepatocellular carcinoma[J]. PLoS One, 2013, 8(5): e65023.
[12]
Wang H, Xu L, Zhu X, et al. Activation of phosphatidylinositol 3-kinase/Akt signaling mediates sorafenib-induced invasion and metastasis in hepatocellular carcinoma[J]. Oncol Rep, 2014, 32(4): 1465-1472.
[13]
Ha TY, Hwang S, Moon KM, et al. Sorafenib inhibits migration and invasion of hepatocellular carcinoma cells through suppression of matrix metalloproteinase expression[J]. Anticancer Res, 2015, 35(4): 1967-1976.
[14]
Wang X, Jiang F, Mu J, et al. Arsenic trioxide attenuates the invasion potential of human liver cancer cells through the demethylation-activated microRNA-491[J]. Toxicol Lett, 2014, 227(2): 75-83.
[15]
Zheng T, Yin D, Lu Z, et al. Nutlin-3 overcomes arsenic trioxide resistance and tumor metastasis mediated by mutant p53 in hepatocellular carcinoma[J]. Mol Cancer, 2014(13): 133.
[16]
Wang GZ, Zhang W, Fang ZT, et al. Arsenic trioxide: marked suppression of tumor metastasis potential by inhibiting the transcription factor Twist in vivo and in vitro[J]. J Cancer Res Clin Oncol, 2014, 140(7): 1125-1136.
[17]
Lin CC, Hsu C, Hsu CH, et al. Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial[J]. Invest New Drugs, 2007, 25(1): 77-84.
[18]
Chang L, Graham PH, Hao J, et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance[J]. Cell Death Dis, 2013(4): e875.
[19]
Dong S, Kong J, Kong F, et al. Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through Akt and ERK signaling pathways[J]. J Transl Med, 2013(11): 273.
[20]
Zhang J, Yao H, Song G, et al. Regulation of epithelial-mesenchymal transition by tumor-associated macrophages in cancer[J]. Am J Transl Res, 2015, 7(10): 1699-1711.
[1] 中国医师协会肝癌专业委员会. 肝细胞癌伴微血管侵犯诊断和治疗中国专家共识(2024版)[J/OL]. 中华普通外科学文献(电子版), 2024, 18(05): 313-324.
[2] 李华志, 曹广, 刘殿刚, 张雅静. 不同入路下行肝切除术治疗原发性肝细胞癌的临床对比[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 52-55.
[3] 常小伟, 蔡瑜, 赵志勇, 张伟. 高强度聚焦超声消融术联合肝动脉化疗栓塞术治疗原发性肝细胞癌的效果及安全性分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 56-59.
[4] 屈翔宇, 张懿刚, 李浩令, 邱天, 谈燚. USP24及其共表达肿瘤代谢基因在肝细胞癌中的诊断和预后预测作用[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 659-662.
[5] 公宇, 廖媛, 尚梅. 肝细胞癌TACE术后复发影响因素及预测模型建立[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 818-824.
[6] 李一帆, 朱帝文, 任伟新, 鲍应军, 顾俊鹏, 张海潇, 曹耿飞, 阿斯哈尔·哈斯木, 纪卫政. 血GP73水平在原发性肝癌TACE疗效评价中的作用[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 825-830.
[7] 刘敏思, 李荣, 李媚. 基于GGT与Plt比值的模型在HBV相关肝细胞癌诊断中的作用[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 831-835.
[8] 焦振东, 惠鹏, 金上博. 三维可视化结合ICG显像技术在腹腔镜肝切除术治疗复发性肝癌中的应用[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 859-864.
[9] 陈晓鹏, 王佳妮, 练庆海, 杨九妹. 肝细胞癌VOPP1表达及其与预后的关系[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 876-882.
[10] 袁雨涵, 杨盛力. 体液和组织蛋白质组学分析在肝癌早期分子诊断中的研究进展[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 883-888.
[11] 吴警, 吐尔洪江·吐逊, 温浩. 肝切除术前肝功能评估新进展[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 889-893.
[12] 邓万玉, 陈富, 许磊波. 肝硬化与非肝硬化乙肝相关性肝癌患者术后无复发生存比较及其影响因素分析[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(05): 670-674.
[13] 王向前, 李清峰, 陈磊, 丘文丹, 姚志成, 李熠, 吴荣焕. 姜黄素抑制肝细胞癌索拉非尼耐药作用及其调控机制[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(05): 729-735.
[14] 龚财芳, 赵俊宇, 游川. 围手术期肠内营养在肝癌肝切除患者中有效性及安全性的Meta分析[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(04): 551-556.
[15] 张杰, 田广磊, 陈雄. 基于生物信息学分析探讨肝癌BRD4与预后关系及其ceRNA调控网络构建[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(04): 568-576.
阅读次数
全文


摘要


AI


AI小编
你好!我是《中华医学电子期刊资源库》AI小编,有什么可以帮您的吗?