Zhang Hao, Wang Qingqing, Liu Jun, Cao Haoqiang
Department of General Surgery, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314001, P.R. China.
Oncol Lett. 2018 Jun;15(6):9377-9384. doi: 10.3892/ol.2018.8536. Epub 2018 Apr 18.
Long-term sorafenib treatment triggers resistance to chemotherapy in patients with hepatocellular carcinoma (HCC). In order to investigate the mechanisms of sorafenib resistance in HCC, the aim of the present study was to develop a resistant human liver cell line via long-term exposure to sorafenib. The cytotoxicity cell counting kit-8 assay was used to evaluate drug sensitivity. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to examine the molecular mechanisms underpinning sorafenib resistance. Migratory and invasive properties in resistant cells were assessed using Transwell assays. The results from the present study revealed that resistant cells became insensitive to sorafenib treatment and exhibited increased migratory and invasive capacities. Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway and epithelial-mesenchymal transition was characteristic of resistant cells. The use of LY294002, a PI3K inhibitor, was able to suppress the activation of Akt and extracellular signal-regulated kinase 1/2, attenuated the migratory and invasive capacities of resistant cells. Data from the present study indicates that inhibition of the PI3K signaling pathway with LY294002 exerts suppressive effects on sorafenib resistance and provides an attractive novel therapeutic regime in patients with advanced HCC.
长期使用索拉非尼治疗会引发肝细胞癌（HCC）患者对化疗产生耐药性。为了探究HCC中索拉非尼耐药的机制，本研究的目的是通过长期暴露于索拉非尼来建立一种耐药的人肝癌细胞系。采用细胞毒性计数试剂盒-8法评估药物敏感性。采用逆转录定量聚合酶链反应和蛋白质印迹法检测索拉非尼耐药的分子机制。使用Transwell实验评估耐药细胞的迁移和侵袭能力。本研究结果显示，耐药细胞对索拉非尼治疗不敏感，并表现出增强的迁移和侵袭能力。磷脂酰肌醇-3-激酶（PI3K）/Akt信号通路的激活和上皮-间质转化是耐药细胞的特征。使用PI3K抑制剂LY294002能够抑制Akt和细胞外信号调节激酶1/2的激活，减弱耐药细胞的迁移和侵袭能力。本研究数据表明，用LY294002抑制PI3K信号通路对索拉非尼耐药具有抑制作用，并为晚期HCC患者提供了一种有吸引力的新型治疗方案。
