索拉非尼通过上调p53和抑制FoxM1来抑制人肝癌细胞的增殖和侵袭。
Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1.
作者信息
Wei Ji-chao, Meng Fan-di, Qu Kai, Wang Zhi-xin, Wu Qi-fei, Zhang Ling-qiang, Pang Qing, Liu Chang
机构信息
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
出版信息
Acta Pharmacol Sin. 2015 Feb;36(2):241-51. doi: 10.1038/aps.2014.122. Epub 2015 Jan 5.
AIM
Forkhead box M1 (FoxM1) is a transcription factor that plays important roles in the pathogenesis and progression of human cancers, including hepatocellular carcinoma (HCC). The aim of this study was to examine the involvement of FoxM1 in the anti-cancer action of sorafenib, a multikinase inhibitor, in human HCC cells.
METHODS
HCC cell lines HepG2 and HuH-7 were tested. Cell viability was examined using MTT assay and cell invasion was determined with Transwell migration assay. The relevant mRNA expression was determined with RT-PCR, and the proteins were detected using Western blotting and immunofluorescence assays. RNA interference was used to modify the expression of p53 and FoxM1. HuH-7 cell line xenograft mice were used for in vivo study, which were treated with sorafenib (40 mg/kg, po) daily for 3 weeks.
RESULTS
Sorafenib (2-20 μmol/L) inhibited the proliferation of the cells in dose- and time-dependent manners with an IC50 value of nearly 6 μmol/L at 48 h. Sorafenib (6 μmol/L) markedly suppressed the cell invasion. Furthermore, sorafenib (2-6 μmol/L) dose-dependently decreased the expression of FoxM1, MMP-2, and Ki-67, and up-regulated that of p53 in the cells. Silencing p53 abolished the decrease of FoxM1 and increase of p53 in sorafenib-treated cells. Silencing FoxM1 significantly reduced the expression of MMP-2 and Ki-67, and enhanced the anti-proliferation action of sorafenib in the cells, whereas overexpression of FoxM1 increased the expression of MMP-2 and Ki-67, and abrogated the anti-proliferation action of sorafenib. In the xenograft mice, sorafenib administration decreased the tumor growth by 40%, and markedly increased the expression of p53, and decreased the expression of FoxM1, MMP-2, and Ki-67 in tumor tissues.
CONCLUSION
Sorafenib inhibits HCC proliferation and invasion by inhibiting MMP-2 and Ki-67 expression due to up-regulation of P53 and suppressing FoxM1.
目的
叉头框M1（FoxM1）是一种转录因子，在包括肝细胞癌（HCC）在内的人类癌症的发病机制和进展中发挥重要作用。本研究的目的是探讨FoxM1在多激酶抑制剂索拉非尼对人肝癌细胞的抗癌作用中的参与情况。
方法
对肝癌细胞系HepG2和HuH-7进行检测。使用MTT法检测细胞活力，采用Transwell迁移试验测定细胞侵袭能力。用RT-PCR测定相关mRNA表达，用蛋白质印迹法和免疫荧光试验检测蛋白质。采用RNA干扰技术改变p53和FoxM1的表达。将HuH-7细胞系异种移植小鼠用于体内研究，每天用索拉非尼（40mg/kg，口服）治疗3周。
结果
索拉非尼（2-20μmol/L）以剂量和时间依赖性方式抑制细胞增殖，48小时时IC50值接近6μmol/L。索拉非尼（6μmol/L）显著抑制细胞侵袭。此外，索拉非尼（2-6μmol/L）剂量依赖性地降低细胞中FoxM1、MMP-2和Ki-67的表达，并上调p53的表达。沉默p53消除了索拉非尼处理细胞中FoxM1的降低和p53的增加。沉默FoxM1显著降低MMP-2和Ki-67的表达，并增强索拉非尼对细胞的抗增殖作用，而FoxM1的过表达增加MMP-2和Ki-67的表达，并消除索拉非尼的抗增殖作用。在异种移植小鼠中，给予索拉非尼可使肿瘤生长减少40%，并显著增加肿瘤组织中p53的表达，降低FoxM1、MMP-2和Ki-67的表达。
结论
索拉非尼通过上调P53抑制FoxM1，从而抑制MMP-2和Ki-67的表达，进而抑制肝癌细胞的增殖和侵袭。
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