我国是原发性肝癌的高发国，每年我国肝癌死亡总数占全世界45%。Ferroportin1(FPN1)是目前已知的唯一一个由细胞内向细胞外转运铁的细胞膜蛋白，近年来研究发现，FPN1的下调与原发性肝癌预后及恶性程度呈高度负相关，但是FPN1与肝细胞癌的发生关系研究至今还处于空白。我们前期研究发现，超过1/10的FPN1基因突变鼠会自发肝细胞癌，且FPN1在药物诱发肝癌组织中低表达。本研究将进一步从基因突变鼠、药物诱发肝癌模型，鼠原代肝细胞体外实验三个方面，深入探讨FPN1的下调在原发性肝癌发生中的促进作用，以及这一作用是否依赖细胞内铁累积，并探索FPN1下调是否通过激活JAK2/STAT3通路，并启动下游癌基因转录而发挥促肿瘤发生作用。我们研究还发现，药物硼替佐米可通过抑制hepcidin诱导的FPN1内化降解而上调FPN1的表达，进而我们将探索硼替佐米在预防肝癌发生的应用前景。

The mortality of hepatocellular carcinoma in China was more than 45% of all over the world. As known, Ferroportin1 (FPN1) was the only protein on cell menbrane to transport iron out of cells. As others' research, the downregulation of FPN1 was negative relation to outcome and morbidite of hepatocellular carcinoma (HCC). As ours research, more than ten percent of FPN1 mutation mice can apontaneous hepatocellular carcinoma, and the expression of FPN1 was lower in liver tissue of drug-induced HCC model than control. FPN1 mutation mice, drug-induced HCC model and separated liver cells was used to figure out the function of FPN1 downregulation in HCC oncogenesis. And if JAK2/stat3 pathways was activated independing on iron overload. Further more, we will investigate the therapeutic potential of a protesome inhibitor, botezomib, which through inhibiting hepcidin-induced degradation of FPN1.