Molecular Mechanism For The Antiviral And Antitumor Acti

干扰素α（IFN-α）治疗是目前病毒性肝炎的主要选择，也是肝细胞癌（HCC）的有希望的治疗方法。然而，IFN α的抗病毒和抗肿瘤活性的分子机制尚不清楚。原代小鼠和大鼠肝细胞对IFN α刺激的反应较差。本项目的目的是研究IFN α信号通路在原代人肝细胞。我们证明，原代人肝细胞非常好地响应IFN α刺激，如通过激活多个信号转导和激活转录因子（STAT）1，2，3 - 5和多个基因所证明的。IFN α上调超过50个基因超过2倍，下调超过20个基因50%。上调的基因包括抗病毒基因（MxA、OAS、PKR）、肿瘤抑制基因/促凋亡基因（IRF-1、Mac-2BP、I 01 F6、STAT 1、钙蛋白酶、9-27等）和黄曲霉毒素B1醛还原酶基因。下调的基因包括c-myc和HGF受体（c-Met）。c-Met的下调是由于IFN-α通过下调Sp1结合抑制c-Met启动子，导致HGF诱导的信号和细胞增殖减弱。

Interferon alpha (IFN-alpha) therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the antiviral and antitumor activity of IFN alpha are not clear. Primary mouse and rat hepatocytes respond poorly to IFN alpha stimulation. The aim of this project is to examine the IFN alpha signal pathway in primary human hepatocytes. We demonstrate that primary human hepatocytes respond very well to IFN alpha stimulation as demonstrated by activation of multiple signal transducer and activator transcription factors (STAT) 1, 2, 3 5 and multiple genes. IFN alpha upregulates more than 50 genes by over 2 fold and downregulates more than 20 genes by 50%. The upregulated-genes include antiviral genes (MxA, OAS, PKR), tumor suppressors/proapoptotic genes (IRF-1, Mac-2BP, I01F6, STAT1, calpain, 9-27, etc), and the aflatoxin B1 aldehyde reductase gene. The downregulated-genes include c-myc and HGF receptor (c-Met). Downregulation of c-Met is due to IFN-alpha suppression of the c-Met promoter through downregulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation.