TNF-alpha is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma
TNF-alpha is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma
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TNF-α是克服肝细胞癌索拉非尼耐药的潜在治疗靶点
DOI：
10.1016/j.ebiom.2018.12.047
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发表时间：
2019-02-01
期刊：
影响因子：
11.1
通讯作者：
Chen, Yajin
中科院分区：
文献类型：
--
作者：
Tan, Wenliang;Luo, Xuan;Chen, Yajin
背景：肿瘤坏死因子α（TNF-α）在肝细胞癌（HCC）靶向治疗中的作用仍不清楚。本研究旨在阐明靶向肿瘤坏死因子-α克服索拉非尼耐药hcch.Methods：肿瘤坏死因子-α表达与预后的相关性进行了分析，在62例肝癌患者接受手术切除，随后接受辅助索拉非尼治疗。在不同的HCC细胞系中确定TNF-α表达与索拉非尼敏感性的关系。索拉非尼和乌司他丁，这可以抑制肿瘤坏死因子-α表达，对HCC的联合治疗效果进行了检查，在体外和在vivo.Findings：高肿瘤坏死因子-α表达与肝癌患者接受辅助索拉非尼手术后的不良结局。体外实验表明，TNF-α通过诱导上皮间质转化（EMT）促进肝癌细胞对索拉非尼的耐药。值得注意的是，目前的研究表明，索拉非尼对TNF-α的表达和分泌没有显著影响，索拉非尼对逆转具有高TNF-α表达的HCC细胞中的EMT的有效性有限。抑制肿瘤坏死因子-α的表达与乌司他丁显着增强索拉非尼对肝癌细胞的抗肿瘤作用与高表达的肿瘤坏死因子-α在体外和体内。Interpretation：我们的研究结果表明，肿瘤坏死因子-α可能作为一种新的预测索拉非尼敏感性肝癌患者。索拉非尼联合乌司他丁可提高TNF-α高表达的HCC患者的治疗效果。(C)2018作者由爱思唯尔公司出版
Background: The role of tumor necrosis factor alpha (TNF-alpha) in targeted therapy for hepatocellular carcinoma (HCC) remains largely unknown. The current study aimed to clarify the mechanistic effects of targeting TNF-alpha to overcome sorafenib resistance in HCC.Methods: A correlation of TNF-alpha expression with the prognosis was analyzed in 62 HCC patients who underwent surgical resection and subsequent received adjuvant sorafenib treatment. The relation of TNF-alpha expression and sorafenib sensitivity was determined in different HCC cell lines. The combined therapeutic effects of sorafenib and ulinastatin, which could inhibit TNF-alpha expression, on HCC were examined in vitro and in vivo.Findings: High TNF-alpha expression was correlated with poor outcomes in HCC patients who received adjuvant sorafenib after surgery. In vitro experiments showed that TNF-alpha promotes HCC cell resistant to sorafenib through inducing epithelial-mesenchymal transition (EMT). Notably, the current study revealed that sorafenib has no significant influence on the expression and secretion of TNF-alpha, and sorafenib had limited effectiveness on reversing EMT in HCC cells with high TNF-alpha expression. Inhibiting the expression of TNF-alpha with ulinastatin significantly enhanced the anti-tumor effect of sorafenib on HCC cells with high expression of TNF-alpha in vitro and in vivo.Interpretation: Our findings indicate that TNF-alpha may serve as a novel predictor of sorafenib sensitivity in HCC patients. Sorafenib combined with ulinastatin may improve the effectiveness of treatment of HCC in patients with high expression of TNF-alpha. (C) 2018 The Authors. Published by Elsevier B.V.