A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis.
A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis.
复制标题
DOI：
10.1038/s41467-021-27452-9
复制
发表时间：
2021-12-17
影响因子：
16.6
通讯作者：
Ma L
中科院分区：
文献类型：
--
作者：
Yao F;Deng Y;Zhao Y;Mei Y;Zhang Y;Liu X;Martinez C;Su X;Rosato RR;Teng H;Hang Q;Yap S;Chen D;Wang Y;Chen MM;Zhang M;Liang H;Xie D;Chen X;Zhu H;Chang JC;You MJ;Sun Y;Gan B;Ma L
对铁凋亡的认识不断增加，提示了铁凋亡在癌症中的作用和治疗潜力，但尚未转化为有效的治疗。肝癌，主要是肝细胞癌（HCC），是高度致命的，治疗选择有限。LIFR在HCC中经常下调。在这里，通过研究肝细胞特异性和可诱导的Lifr基因敲除小鼠，我们表明，Lifr的损失促进肝脏肿瘤的发生，并赋予耐药性药物诱导的铁凋亡。从机制上讲，LIFR的缺失通过SHP 1激活NF-κB信号传导，导致铁螯合细胞因子LCN 2的上调，其消耗铁并使对铁凋亡诱导剂不敏感。值得注意的是，LCN 2中和抗体增强了索拉非尼对具有低LIFR表达和高LCN 2表达的HCC患者来源的异种移植肿瘤的铁凋亡诱导和抗癌作用。因此，抗LCN 2疗法是通过靶向铁凋亡来改善肝癌治疗的有希望的方法。白血病抑制因子受体（LIFR）在肝癌中经常下调。在此，作者表明LIFR的缺失促进肝脏肿瘤发生，并通过NF-κ B介导的铁螯合细胞因子LCN 2的上调而赋予对药物诱导的铁凋亡的抗性。
The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis. Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in liver cancer. Here the authors show that loss of LIFR promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis through NF-κB-mediated upregulation of iron-sequestering cytokine LCN2.
登录
查看更多内容
影响因子：
11.2
作者：
Chakraborty, Subhankar;Kaur, Sukhwinder;Guha, Sushovan;Batra, Surinder K.
通讯作者：
Batra, Surinder K.
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
6
作者：
Bu, De-xiu;Hemdahl, Anne-Louise;Yan, Zhong-qun
通讯作者：
Yan, Zhong-qun
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M