Hubei Hongshan Laboratory, College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Nat Commun. 2021 Dec 17;12(1):7333. doi: 10.1038/s41467-021-27452-9.
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.
铁死亡知识的不断增加表明了铁死亡在癌症中的作用和治疗潜力，但尚未转化为有效的治疗方法。肝癌主要是肝细胞癌（HCC），治疗选择有限，致死率很高。LIFR 在 HCC 中经常下调。在这里，通过研究肝细胞特异性和诱导型 Lifr 敲除小鼠，我们表明 Lifr 的缺失促进了肝肿瘤的发生，并赋予了对药物诱导的铁死亡的抗性。在机制上，LIFR 的缺失通过 SHP1 激活 NF-κB 信号通路，导致铁螯合细胞因子 LCN2 的上调，从而耗尽铁并使铁死亡诱导剂不敏感。值得注意的是，LCN2 中和抗体增强了索拉非尼对 HCC 患者来源异种移植肿瘤的铁死亡诱导和抗癌作用，这些肿瘤的 LIFR 表达低，LCN2 表达高。因此，抗 LCN2 治疗通过靶向铁死亡是改善肝癌治疗的一种有前途的方法。
