Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
J Exp Med. 2019 Apr 1;216(4):950-965. doi: 10.1084/jem.20180900. Epub 2019 Mar 15.
Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver was also found to be effective in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis promoted by iron overload. In addition, dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human HCC, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis.
肝脏铁过载是肝细胞癌（HCC）进展的一个风险因素，尽管这种关联的分子机制仍不清楚。我们现在表明，铁感应泛素连接酶 FBXL5 是小鼠肝脏发生癌变中以前未被识别的肿瘤抑制因子。FBXL5 缺失引起的肝细胞铁过载导致氧化应激、组织损伤、炎症和肝细胞的代偿性增殖，并继而促进化学致癌物诱导的肝癌发生。在病毒诱导的 HCC 模型中也发现，FBXL5 缺失在肝脏中的促肿瘤作用是有效的。因此，FBXL5 缺陷小鼠构成了首个由铁过载促进的肝脏癌变的基因工程小鼠模型。此外，发现 FBXL5 介导的细胞内铁稳态失调与人类 HCC 的预后不良相关，表明 FBXL5 在防御肝癌发生中起着关键作用。
