Genetic network analysis of INF-α treatment in hepatitis C virus-related hepatocellular carcinoma

肝细胞癌（HCC）是第五大最常见的恶性疾病，每年在全世界造成约100万人死亡。肝细胞癌在亚洲和非洲更为常见。约80%的HCC患者同时伴有肝硬化。在这项研究中，我们打算通过MAPK途径描述IFN-α在人肝癌细胞系中抗增殖作用的快速反应。并利用siRNA技术研究了MEK和ERK磷酸化的增强作用，通过芯片阻断MEK和ERK磷酸化抑制及下游基因激活抑制通路。干扰素α (IFN-α)对肝细胞癌的潜在抗增殖作用及其生长抑制机制尚不清楚。在这项研究中，我们描述了IFN-α通过MAPK途径在人肝癌细胞系HepG2、Hep3B、HuH7和PLC/PRF/5中抗增殖作用的快速反应。我们发现IFN-α受体表达量最多的PLC/PRF/5对IFN-α的生长抑制高度敏感。IFN-α延缓G1/S转变，无凋亡迹象。IFN-α在5分钟内抑制细胞外信号调节激酶（ERK）和丝裂原活化的ERK调节激酶（MEK）的磷酸化，但不抑制Raf的磷酸化。STAT1和JAK1的下调抑制了ERK和MEK磷酸化的降低，减轻了IFN-α对生长的抑制作用。这些结果表明，IFN-α通过IFN-α受体下游的JAK/STAT通路诱导快速的抗增殖信号通路，并可能通过与MEK/ERK通路的串扰抑制生长刺激信号通路。通过表达谱分析，我们确定了常见的下调或上调基因及其转录调控元件。

Hepatocellular carcinoma (HCC) is the fifth most common malignant disorder and causes about 1 million deaths a year worldwide. Hepatocellular carcinoma is more common in Asia and Africa. About 80% of patients with HCC also have liver cirrhosis. In this study, we intend to delineate the rapid response of the anti-proliferative action of IFN-α via the MAPK pathway in human hepatocellular carcinoma cell lines. And using siRNA technology, we investigated the enhancement of phosphorylation of MEK and ERK and blocked the inhibition of phosphorylation of MEK and ERK and downstream gene activation and suppression pathway by microarray. The potential anti-proliferation effict of interferonalpha (IFN-α) against hepatocellular carcinoma and its growth inhibitory mechanisms remain poorly understood. In this study, we delineated the rapid response of the anti-proliferative action of IFN-α via the MAPK pathway in human hepatocellular carcinoma cell lines HepG2, Hep3B, HuH7, and PLC/PRF/5. We found that PLC/PRF/5, which had the most abundant expression of IFN-α receptors, was highly sensitive to growth inhibition by IFN-α. IFN-α retarded G1/S transition with no evidence of apoptosis. IFN-α suppressed the phosphorylation of both extracellular signal-regulated kinase (ERK) and mitogen-activated ERK-regulating kinase (MEK), but not Raf, within 5 min. Knockdown of STAT1 and JAK1 suppressed the reduction of phosphorylation both of ERK and MEK and diminished the growth inhibition by IFN-α. These results suggest that IFN-α induces rapid antiproliferative signaling via JAK/STAT pathway downstream of IFN-α receptors and may inhibit the growth stimulation signaling by cross-talk with the MEK/ERK pathway. By expression profiling, we identified common down regulated or up-regulated genes and their transcriptional regulatory elements.