Proteomic Profile of Sorafenib Resistance in Hepatocellular Carcinoma; GRP78 Expression Is Associated With Inferior Response to Sorafenib
Proteomic Profile of Sorafenib Resistance in Hepatocellular Carcinoma; GRP78 Expression Is Associated With Inferior Response to Sorafenib
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DOI：
10.21873/cgp.20159
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发表时间：
2019-11-01
影响因子：
2.5
通讯作者：
Wu, Ting-Feng
中科院分区：
文献类型：
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作者：
Feng, Yin-Hsun;Tung, Chao-Ling;Wu, Ting-Feng
背景/目标：晚期肝细胞癌（HCC）患者的结局仍然很差，治疗选择有限，包括索拉非尼，这是第一种被证明可以延长晚期HCC患者生存期的抗癌药物。然而，尚未报道索拉非尼的临床有用的预测生物标志物。材料与方法：我们利用二维凝胶电泳结合质谱法，通过使用索拉非尼耐药肝癌细胞系Huh 7的调节来寻找失调蛋白。对60例接受索拉非尼治疗的HCC患者的肿瘤样本进行分析，并与生存结局进行相关性分析。结果如下：比较蛋白质组学显示三种蛋白质，包括78 kDa葡萄糖相关蛋白（GRP 78）、14-3-3 β和热休克蛋白90 β（HSP 90 β）。这三种蛋白在索拉非尼耐药的Huh 7细胞中过表达。在来自用索拉非尼治疗的患者的HCC肿瘤样品中，73%的肿瘤样品具有高表达的GRP 78，18%具有高表达的14-3-3 β，85%具有高表达的HSP 90，3。其中，GRP 78与接受索拉非尼治疗的HCC患者的最短无进展生存期相关。结论：GRP 78可作为肝癌患者索拉非尼治疗的预测性生物标志物。旨在抑制GRP 78相关途径的策略可能会克服索拉非尼耐药性。
Background/Aim: The outcome of patients with advanced hepatocellular carcinoma (HCC) remains poor and therapeutic options, including sorafenib, the first anticancer drug proved to prolong survival in patients with advanced HCC, are limited. However, no clinically useful predictive biomarker for sorafenib has been reported. Materials and Methods: We exploited two-dimensional gel electrophoresis coupled with mass spectrometry to find deregulated proteins by using conditioning of a sorafenib-resistant HCC cell line, Huh7. Tumor samples from 60 patients with HCC treated with sorafenib were analyzed and correlated with survival outcome. Results: Comparative proteomics indicated three proteins including, 78 kDa glucose related protein (GRP78), 14-3-3 epsilon, and heat shock protein 90 beta (HSP90 beta). The three proteins were over-expressed in sorafenib-resistant Huh7 cells. In HCC tumor samples from patients treated with sorafenib, 73% of tumor samples had a high expression of GRP78, 18% had high 14-3-3 epsilon expression and 85% had high HSP90,3 expression. Among these, GRP78 was associated with the shortest progression free survival of HCC patients treated with sorafenib. Conclusion: GRP78 can be a predictive biomarker in HCC patients treated with sorafenib. Strategies designed to inhibit the GRP78-related pathway may overcome sorafenib resistance.