Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma.
Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma.
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DOI：
10.1186/s13046-021-02208-x
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发表时间：
2022-01-03
期刊：
影响因子：
--
通讯作者：
Feng Y
中科院分区：
文献类型：
--
作者：
Lu Y;Chan YT;Tan HY;Zhang C;Guo W;Xu Y;Sharma R;Chen ZS;Zheng YC;Wang N;Feng Y
索拉非尼的耐药性极大地限制了肝细胞癌（HCC）患者的治疗获益。microRNAs（miRNAs）参与了耐药性的形成。与索拉非尼治疗的临床结局相关的关键miRNA调控因子及其分子机制仍有待鉴定。通过分析公开可用的数据库和内部人HCC组织，评估索拉非尼耐药HCC中miRNA相关表观遗传学变化的临床意义。研究了miR-23 a-3 p在体外和体内的生物学功能。通过蛋白质组学和生物信息学分析探讨miR-23 a-3 p的调控机制。采用荧光素酶报告基因分析和染色质免疫沉淀（ChIP）分析验证miR-23 a-3 p与其靶点的结合关系。我们发现miR-23 a-3 p是HCC中最显著的miRNA，在索拉非尼无应答者中过表达，提示生存率低和HCC复发。索拉非尼耐药细胞表现出以ETS原癌基因1（ETS 1）依赖性方式增加的miR-23 a-3 p转录。miR-23 a-3 p的CRISPR-Cas9敲除改善了HCC细胞以及原位HCC肿瘤中的索拉非尼应答。蛋白质组学分析表明，索拉非尼诱导的铁凋亡是miR-23 a-3 p抑制的关键途径，减少了细胞铁积累和脂质过氧化。miR-23 a-3 p直接靶向ACSL 4的3′-非翻译区（UTR），ACSL 4是铁凋亡的关键正调控因子。miR-23 a-3 p抑制剂拯救了ACSL 4表达并诱导索拉非尼处理得HCC细胞中得视铁细胞死亡. ACSL 4 siRNA和miR-23 a-3 p抑制剂的联合给药消除了索拉非尼的应答。我们的研究表明，ETS 1/miR-23 a-3 p/ACSL 4轴通过调节铁凋亡而有助于HCC中索拉非尼耐药。我们的研究结果表明，miR-23 a-3 p可能是一个潜在的目标，以提高索拉非尼在肝癌患者的反应。在线版本包含补充材料，可通过10.1186/s13046-021-02208-x获得。
Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients. The online version contains supplementary material available at 10.1186/s13046-021-02208-x.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
--
作者：
Ohta K;Hoshino H;Wang J;Ono S;Iida Y;Hata K;Huang SK;Colquhoun S;Hoon DS
通讯作者：
Hoon DS
DOI：
10.1007/s10495-020-01627-z
发表时间：
2020-10
期刊：
Apoptosis : an international journal on programmed cell death
影响因子：
--
作者：
Lee YS;Kalimuthu K;Park YS;Luo X;Choudry MHA;Bartlett DL;Lee YJ
通讯作者：
Lee YJ
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
LXR 激活通过激活 microRNA-378a 转录增强 HCC 中索拉非尼的敏感性
影响因子：
12.4
作者：
Lin, Zhongjie;Xia, Shunjie;Cai, Xiujun
通讯作者：
Cai, Xiujun