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

INF-α治疗丙型肝炎病毒相关性肝细胞癌的基因网络分析

• 批准号: 15310137
• 负责人: UCHIDA Kazuhiko
• 金额: $ 5.18万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15310137/
• 关键词: interferon; IFNα; gene expression; microarray; signal cascade; 遺伝子ネットワーク

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.

肝细胞癌（HCC）是第五常见的恶性疾病，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。大约80%的HCC患者同时患有肝硬化。在这项研究中，我们打算描绘干扰素-α的抗增殖作用的快速反应，通过MAPK途径在人肝癌细胞系。并利用siRNA技术，通过基因芯片研究了MEK和ERK磷酸化的增强作用，以及对MEK和ERK磷酸化抑制及下游基因激活和抑制通路的阻断作用。α干扰素（IFN-α）对肝癌细胞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，我们描绘了IFN-α通过MAPK途径在人肝癌细胞系HepG 2，Hep 3B，HuH 7和PLC/PRF/5中的抗增殖作用的快速反应。结果表明，表达IFN-α受体最多的PLC/PRF/5细胞对IFN-α的生长抑制作用高度敏感。IFN-α阻滞G1/S转换，但无凋亡迹象。5 min内，IFN-α可抑制细胞外信号调节激酶（ERK）和有丝分裂原激活的ERK调节激酶（MEK）的磷酸化，但对Raf无影响。STAT 1和JAK 1的敲低可抑制ERK和MEK磷酸化的减少，并减弱IFN-α的生长抑制作用。这些结果表明，IFN-α通过IFN-α受体下游的JAK/STAT途径诱导快速的抗增殖信号，并可能通过与MEK/ERK途径的串扰抑制生长刺激信号。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。

项目成果

Genetic and environmental determinants of risk for cholangiocarcinoma via Opisthorchis viverrini in a densely infested area in Nakhon Phanom, northeast Thailand

• DOI: 10.1002/ijc.21146
• 发表时间: 2005-12-10
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Honjo, S;Srivatanakul, P;Miwa, M
• 通讯作者: Miwa, M

Gene expression profile correlates with the morphology and metastasis characteristics of renal cell carcinoma cell lines

基因表达谱与肾细胞癌细胞系的形态和转移特征相关

• 发表时间: 2005
• 期刊: Oncology Reports 13
• 作者: Ami;Y.;Uchida;K.et al.
• 通讯作者: K.et al.

Gene Expression Profiling Identifies Platelet-Derived Growth Factor as a Diagnostic Molecular Marker for Papillary Thyroid Carcinoma

• DOI: 10.1158/1078-0432.ccr-0807-03
• 发表时间: 2004-03
• 期刊: Clinical Cancer Research
• 影响因子: 11.5
• 作者: Yukiko Yano;N. Uematsu;T. Yashiro;H. Hara;E. Ueno;M. Miwa;G. Tsujimoto;Y. Aiyoshi;K. Uchida

Naoya Uematsu, Yukihiro Maki, Masahiro Okamoto, Kazuhiko Uchida: "Analysis of genetic networks using time-course data of gene expression profiling"Cytometry Research. 13. 1-7 (2003)

Naoya Uematsu、Yukihiro Maki、Masahiro Okamoto、Kazuhiko Uchida：“使用基因表达谱的时间过程数据分析遗传网络”细胞计数研究。

Uchida, K: "Gene amplification and cancer"Nature Encyclopedia of Human Genome. 2. 593-598 (2003)

Uchida, K：“基因扩增与癌症”人类基因组自然百科全书。