Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis

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 previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload evoked by FBXL5 ablation gives rise to oxidative stress, tissue damage, inflammation and compensatory proliferation in hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting effect of FBXL5 deficiency in the liver is also operative in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis induced by iron overload. Dysregulation of FBXL5-mediated cellular iron homeostasis was also found to be associated with poor prognosis in human HCC, implicating FBXL5 plays a significant role in defense against hepatocarcinogenesis. Total RNA was extracted from the nontumor and tumor tissue of an Alb-Cre/Fbxl5F/F male mouse (nontumor, n = 5; tumor, n = 5) or two littermate control Fbxl5F/F mice (nontumor, n = 6; tumor, n = 6) at 45 weeks of age.

肝脏铁过载是肝细胞癌（hepatocellular carcinoma, HCC）进展的危险因素，尽管二者关联的分子机制至今尚未阐明。本研究证实，铁感应泛素连接酶（iron-sensing ubiquitin ligase）FBXL5是小鼠肝脏癌变进程中此前未被发现的抑癌因子。FBXL5敲除诱发的肝细胞铁过载，可引发肝细胞内氧化应激、组织损伤、炎症反应及代偿性增殖，进而促进化学致癌物暴露诱导的肝脏癌变。肝脏FBXL5缺失的促瘤效应在病毒诱导的肝细胞癌模型中同样成立。因此，FBXL5敲除小鼠是首个由铁过载诱导的肝脏癌变基因工程小鼠模型（genetically engineered mouse model）。研究还发现，FBXL5介导的细胞铁稳态（cellular iron homeostasis）失衡与人类肝细胞癌的不良预后显著相关，提示FBXL5在抵御肝脏癌变过程中发挥关键作用。在小鼠45周龄时，从1只Alb-Cre/Fbxl5F/F雄性敲除小鼠的非肿瘤组织与肿瘤组织中提取总RNA（非肿瘤组织样本量n=5，肿瘤组织样本量n=5），同时从2只同窝对照Fbxl5F/F小鼠中提取对应组织的总RNA（非肿瘤组织样本量n=6，肿瘤组织样本量n=6）。