Regorafenib reverses HGF-induced sorafenib resistance by inhibiting epithelial-mesenchymal transition in hepatocellular carcinoma
Regorafenib reverses HGF-induced sorafenib resistance by inhibiting epithelial-mesenchymal transition in hepatocellular carcinoma
复制标题
瑞戈非尼通过抑制肝细胞癌中的上皮间质转化来逆转 HGF 诱导的索拉非尼耐药
DOI：
10.1002/2211-5463.12578
复制
发表时间：
2019-02-01
期刊：
影响因子：
2.6
通讯作者：
Sun, Donglin
中科院分区：
文献类型：
--
作者：
Chen, Weibo;Yang, Junsheng;Sun, Donglin
索拉非尼耐药是晚期肝细胞癌（HCC）患者获得更好结局的主要障碍之一，其中经常观察到肝细胞生长因子（HGF）/间质-上皮转化途径的异常激活。在这里，我们报告肝癌细胞发展索拉非尼耐药后，肝细胞生长因子刺激。此外，HGF激活下游细胞外信号相关激酶（ERK）和信号转导和转录激活因子3（STAT 3）通路，并通过上调HCC细胞中的Snail诱导上皮-间质转化（EMT）。抑制ERK和STAT 3可通过下调Snail和EMT来取消HGF的拯救作用。此外，磷酸肌醇3-激酶/Akt也在HGF处理的HCC细胞中被激活，尽管它对Snail表达没有影响。值得注意的是，我们还发现瑞格非尼通过抑制ERK和STAT 3，随后下调Snail和EMT，逆转HGF诱导的索拉非尼耐药。综上所述，我们的结果表明，HGF通过激活磷酸化（P）-ERK/Snail/EMT和P-STAT 3/Snail/EMT途径诱导索拉非尼耐药。瑞格非尼抑制P-ERK和P-STAT 3可阻断HGF诱导的EMT，从而逆转HGF诱导的索拉非尼耐药。
Sorafenib resistance is one of the major obstacles towards achieving a better outcome in patients with advanced hepatocellular carcinoma (HCC), in which aberrant activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition pathway is frequently observed. Here, we report that HCC cells develop sorafenib resistance following HGF stimulation. Furthermore, HGF activates the downstream extracellular signal-related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) pathway and induces epithelial-mesenchymal transition (EMT) by up-regulating Snail in HCC cells. Inhibition of ERK and STAT3 abolished the rescue effect of HGF by down-regulating Snail and EMT. Moreover, phosphoinositide 3-kinase/Akt was also activated in HGF-treated HCC cells, although it had no effect on Snail expression. Notably, we also found that regorafenib reversed HGF-induced sorafenib resistance by inhibiting ERK and STAT3, and subsequently down-regulating Snail and EMT. Taken together, our results indicate that HGF induces sorafenib resistance by activating phosporylated (P)-ERK/Snail/EMT and P-STAT3/Snail/EMT pathways. Inhibition of P-ERK and P-STAT3 by regorafenib can block HGF-induced EMT, thereby reversing HGF-induced sorafenib resistance.