Inhibition of MMP-2 Expression Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinoma by Suppressing the PI3K/AKT/mTOR Pathway.
Inhibition of MMP-2 Expression Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinoma by Suppressing the PI3K/AKT/mTOR Pathway.
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DOI：
10.3727/096504017x14886444100783
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发表时间：
2017-11-02
影响因子：
3.1
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Tan W;Zhu S;Cao J;Zhang L;Li W;Liu K;Zhong J;Shang C;Chen Y
索拉非尼已被全球批准为晚期肝细胞癌（HCC）患者的标准治疗。然而，肝癌患者对索拉非尼的反应率有限，因为肿瘤复发和转移。因此，寻求与索拉非尼的联合治疗策略是提高抗肿瘤疗效的必要途径。在这里，我们证明MMP-2的表达与肝癌细胞的迁移能力呈正相关。MMP-2表达较高的细胞（SK-HEP-1细胞）对索拉非尼的敏感性低于MMP-2表达较低的细胞（HepG 2细胞）。在MMP-2高表达和低表达的HCC细胞中，SB-3CT和索拉非尼的共处理比单独索拉非尼处理更强烈地抑制细胞的迁移能力。体内细胞转移实验证实了索拉非尼和SB-3CT在减少SK-HEP-1细胞的肺转移方面的协同作用。从机制上讲，我们表明协同抗肿瘤作用可能归因于PI 3 K/AKT/mTOR信号通路的抑制，而不是RAF/MEK/ERK信号通路。综上所述，本研究表明，抑制MMP-2表达可以增强索拉非尼在MMP-2高表达的HCC细胞中的抗肿瘤作用，这可能为提高HCC的治疗效率提供一种新的策略。
Sorafenib has been globally approved as the standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, the response rate of HCC patients to sorafenib is limited because of tumor recurrence and metastasis. Therefore, seeking combined therapeutic strategies with sorafenib is necessary to improve the antitumor efficiency. Here we demonstrated that expression of MMP-2 is positively correlated with the migration ability of HCC cells. Cells with a higher MMP-2 expression (SK-HEP-1 cells) were less sensitive to sorafenib than those with lower MMP-2 expression (HepG2 cells). Cotreatment of cells with SB-3CT and sorafenib more strongly inhibited migration ability than with sorafenib treatment alone in both HCC cells with high and low expression of MMP-2. In vivo cell metastasis experiments confirmed the synergistic effects of sorafenib and SB-3CT in reducing lung metastasis of SK-HEP-1 cells. Mechanistically, we showed that the synergistic antitumor effect may be attributed to inhibition of the PI3K/AKT/mTOR signaling pathway, but not the RAF/MEK/ERK signaling pathway. With these results taken together, the current study demonstrates that inhibiting MMP-2 expression can enhance the antitumor effect of sorafenib in HCC cells with a high MMP-2 expression, which may provide a novel strategy to improve therapeutic efficiency in HCC.