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Analysis of interferon related gene regulation as a proapoptotic function against hepatocellular carcinoma

干扰素相关基因调控对肝细胞癌的促凋亡作用分析

基本信息

批准号：
15590650
负责人：
SAKAGUCHI Kohsaku
金额：
$ 2.18万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590650/
关键词：
Interferon Caspase signal transduction hepatocellular carcinoma アポトーシス 5-FU マイクロアレイ

项目摘要

Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment is recently reported to show marked effects in patients with advanced hepatocellular carcinoma (HCC). IFN alpha 2 is widely provided for chronic liver diseases. But IFN alpha 8 is the most effective subtype to induce apoptosis in several cancer cell lines. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFN alpha 2 or alpha 8 in combination with 5-FU. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRL/5, and HepG2) were tested for apoptosis inducibility by IFN alpha in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. Caspases-3, -9, and especially caspase-8 activities were higher with IFN alpha plus 5-FU than IFN or 5-FU alone. The JAK-STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to both IFN alpha treatments. Inhibition of caspase-3,-8,9,c-Jun N-terminal kinase (JNK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective treatment to decrease apoptotic effects of IFN and/or 5-FU. In JAK1, and ISGF3g-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. Although IFN alpha 8 induced apoptosis more effectively than alpha 2 and showed different cluster in microarray analysis, the JAK-STAT and caspase activation status were similar.We conclude that caspase-8 is the most important factor that controls IFN-and 5-FU- induced apoptosis in hepatoma cell lines.

干扰素（IFN）联合5-氟脲嘧啶（5-FU）治疗晚期肝癌（HCC）近期疗效显著。IFN α 2广泛用于慢性肝病。但IFN α 8是诱导多种癌细胞系凋亡的最有效亚型。在这项研究中，我们研究了IFN α 2或α 8与5-FU联合诱导肝癌细胞系凋亡的分子机制。在不存在或存在5-FU的情况下，测试了五种肝癌细胞系（Hep 3B、Huh 7、HLE、PLC/PRL/5和HepG 2）由IFN α诱导的凋亡。Hep 3B细胞对IFN +5-FU处理最为敏感。与单独的IFN或5-FU相比，IFN α加5-FU的半胱天冬酶-3、-9，尤其是半胱天冬酶-8的活性更高。JAK-STAT途径转录因子ISRE被激活时，更协同5-FU加入到两个IFN α治疗。caspase-3、caspase-8、caspase-9、c-Jun N-末端激酶（JNK）、磷脂酰肌醇3-激酶（PI 3 K）和p38丝裂原活化蛋白激酶（p38 MAPK）的抑制显示，caspase-8抑制是降低IFN和/或5-FU的凋亡效应的最有效的治疗。在JAK 1和ISGF 3g沉默的Hep 3B细胞中，IFN的凋亡诱导和半胱天冬酶-8活化水平，甚至与5-FU组合，被废除。虽然IFN α 8诱导肝癌细胞凋亡的作用强于IFN α 2，且在基因芯片分析中出现不同的聚类，但JAK-STAT和caspase的激活状态相似，提示caspase-8是IFN和5-FU诱导肝癌细胞凋亡的最重要的调控因子。