ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma
ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma
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ACSL4 是肝细胞癌索拉非尼敏感性的预测生物标志物。
DOI：
10.1038/s41401-020-0439-x
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发表时间：
2020-06-15
影响因子：
8.2
通讯作者：
Lu, Guo-dong
中科院分区：
文献类型：
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作者：
Feng, Ji;Lu, Pei-zhi;Lu, Guo-dong
索拉非尼是晚期肝细胞癌（HCC）的一线治疗药物。然而，缺乏有效的生物标志物来预测索拉非尼的敏感性。在这项研究中，我们研究了ACSL 4（一种铁凋亡的正活化酶）在索拉非尼诱导的细胞死亡和HCC患者结局中的作用。ACSL 4蛋白表达与索拉非尼的IC（50）值呈负相关（R =-0.952，P < 0.001）。通过特异性siRNA/sgRNA敲低ACSL 4表达显著减弱了索拉非尼诱导的Huh 7细胞中的脂质过氧化和铁凋亡，并且还挽救了索拉非尼诱导的体内异种移植肿瘤生长抑制。我们从一个以医院为基础的队列中选择了29例手术作为主要治疗和索拉非尼作为术后辅助治疗的HCC患者。索拉非尼治疗完全或部分缓解的HCC患者（66.7%）中，ACSL 4表达高于肿瘤生长稳定或进展的HCC患者（23.5%，P = 0.029）。由于ACSL 4表达与索拉非尼治疗无关，因此它可以作为一种有用的预测生物标志物。综上所述，本研究表明ACSL 4对于索拉非尼诱导的铁凋亡是必不可少的，并且可用于预测HCC中索拉非尼的敏感性。这项研究可能对肝癌的精确治疗产生重要的转化影响。
Sorafenib is the first-line treatment of advanced hepatocellular carcinoma (HCC). However, there is a lack of validated biomarkers to predict sorafenib sensitivity. In this study we investigated the role of ACSL4, a positive-activating enzyme of ferroptosis, in sorafenib-induced cell death and HCC patient outcome. We showed that ACSL4 protein expression was negatively associated with IC(50)values of sorafenib in a panel of HCC cell lines (R = -0.952,P < 0.001). Knockdown of ACSL4 expression by specific siRNA/sgRNA significantly attenuated sorafenib-induced lipid peroxidation and ferroptosis in Huh7 cells, and also rescued sorafenib-induced inhibition of xenograft tumor growth in vivo. We selected 29 HCC patients with surgery as primary treatment and sorafenib as postoperative adjunct therapy from a hospital-based cohort. A high proportion (66.7%) of HCC patients who had complete or partial responses to sorafenib treatment (according to the revised RECIST guideline) had higher ACSL4 expression in the pretreated HCC tissues, compared with those who had stable or progressed tumor growth (23.5%,P = 0.029). Since ACSL4 expression was independent of sorafenib treatment, it could serve as a useful predictive biomarker. Taken together, this study demonstrates that ACSL4 is essential for sorafenib-induced ferroptosis and useful for predicting sorafenib sensitivity in HCC. This study may have important translational impacts in precise treatment of HCC.