Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis
Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis
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DOI：
10.1084/jem.20180900
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发表时间：
2019-04-01
影响因子：
15.3
通讯作者：
Nakayama, Keiichi, I
中科院分区：
文献类型：
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作者：
Muto, Yoshiharu;Moroishi, Toshiro;Nakayama, Keiichi, I
肝铁超载是肝细胞癌（HCC）进展的一个危险因素，尽管这种关联的分子机制尚不清楚。我们现在表明，铁感应泛素连接酶FBXL5在小鼠肝癌发生中是一种以前未被识别的肿瘤抑制因子。FBXL5消融引起的肝细胞铁超载引起氧化应激、组织损伤、炎症和肝细胞代偿性增殖，并由此促进暴露于化学致癌物诱导的肝癌发生。肝脏中FBXL5缺乏的促肿瘤结果在病毒诱导的HCC模型中也被发现是有效的。因此，fbxl5缺陷小鼠构成了铁超载促进肝癌发生的第一个基因工程小鼠模型。此外，FBXL5介导的细胞铁稳态失调被发现与人类HCC预后不良有关，这表明FBXL5在防御肝癌发生中起关键作用。
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.