权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic Regulation Implicates Hypoxia-resistance of Hepatoma Stem Cell Population.

表观遗传调控涉及肝癌干细胞群的耐缺氧性。

基本信息

批准号：
15590662
负责人：
OHTSURU Akira
金额：
$ 2.18万
依托单位：
Nagasaki 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 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590662/
关键词：
hepatoma targeting gene therapy stem cell STI571 NF-kB 肝細胞がん

项目摘要

Terminal growth arrest(TGA) as well as apoptosis plays important role in elimination of dongenic populations after various therapy for hepatoma. We have shown previously that STI571(Gleevec), a selective tyrosine kinase inhibitor, retarded the growth of anaplastic thyroid cancer(ATC) cell lines in vitro and in vivo through selective inhibition of c-Abl tyrosine kinase activity. In the present study, we investigated the ability of Gleevec to modulate the in vitro and in vivo hypoxia response of hepatoma cells. Cell growth assay, colony formation assay and xenograft models were used to quantify Gleevec hypoxiasensitizing effect for hepatoma cell lines HuH7 and HepG2. FACS, Western Blotting and histochemistry techniques were applied to study mechanisms radiation response after Gleevec exposure. Clonogenic analysis demonstrated that Gleevec reduced cell survival after hypoxia stress. Gleevec combined with radiation produced increase in the tumor growth inhibition when compared to treatment with either modality alone in mice bearing ATC xenografts. We investigated several potential mechanisms that may contribute to the enhanced radiation and/or hypoxia responses. Gleevec promoted p21cip 1 accumulation in irradiated ATC cells. Gleevec suppressed radiation-induced c-ABL activation in ARO cells and displayed the induction of terminal growth arrest. Antitumor activity of Gleevec appears to be due to the proliferative growth inhibition associated with the terminal growth arrest associated with senescence. Our study suggest that hepatoma stem cell population is hypoxia resistant and c-Abl suppression is critical for treatment of highly malignant hepatomas.

终末生长停滞(TGA)和细胞凋亡在肝癌治疗后供体种群的消除中起着重要作用。我们以前已经证明，选择性酪氨酸激酶抑制剂STI571(格列卫)通过选择性抑制c-Abl酪氨酸激酶活性，在体外和体内抑制间变性甲状腺癌(ATC)细胞系的生长。在本研究中，我们研究了格列卫对肝癌细胞体外和体内缺氧反应的调节能力。采用细胞生长实验、集落形成实验和异种移植模型，定量检测格列卫对人肝癌细胞株HuH7和HepG2的缺氧增敏作用。应用流式细胞仪、免疫印迹和组织化学技术研究格列卫暴露后的辐射反应机制。克隆形成分析表明，格列卫降低了缺氧应激后细胞的存活率。在携带ATC异种移植的小鼠中，格列卫联合放射治疗与单独使用任何一种方法相比，对肿瘤生长的抑制作用都有所增加。我们研究了几种可能导致辐射和/或缺氧反应增强的潜在机制。格列卫可促进照射后ATC细胞p21cip-1的积聚。格列卫抑制辐射诱导的ARO细胞c-ABL激活，并表现出终末生长停滞的诱导作用。格列卫的抗肿瘤活性似乎是由于与衰老相关的终末生长停滞相关的增殖抑制。我们的研究表明，肝癌干细胞群具有耐缺氧能力，c-Abl抑制对高度恶性肝癌的治疗至关重要。