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

Identify the mechanism of invasion and metastasis of pancreatic cancer and development of novel treatment starategy.

确定胰腺癌侵袭和转移的机制并开发新的治疗策略。

基本信息

批准号：
19591594
负责人：
ISHIKAWA Shinji
金额：
$ 2.83万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

项目摘要

The expression of oxysterol binding protein related protein (ORP) 5 is related to invasion and a poor prognosis in pancreatic cancer patients. ORP5 induced the expression of sterol response element binding protein (SREBP) 2 and activated the downstream gene of sterol response element (SRE). Chromosomal immunoprecipitation (ChIP) using SREBP2 antibody revealed that HDAC5 was one of the downstream genes of SREBP2. The effect of HMG-CoA reductase inhibitors (statins) were analyzed according to the expression level of ORP5. The invasion rate, growth was suppressed in cells that strongly expressed ORP5 in a time and dose dependent manor, but had less effect in cells weakly expressing ORP5, thus suggesting that when the potential of invasion and growth relies on the cholesterol synthesis pathway, it becomes sensitive to HMG-CoA reductase inhibitor. Furthermore, HDAC inhibitor, tricostatin A (TSA), induced the expression of phosphatase and tensin homologue (PTEN) as well when ORP5 was suppressed or the cells were treated with statin. Treatment with both statin and TSA showed a synergistic anti-tumor effect in cells that highly expressed ORP5. Therefore, in some pancreatic cancers, continuous ORP5 expression enhances the cholesterol synthesis pathway and this signal transduction regulates PTEN via HDAC5 expression. This is the first report of a detail mechanism of how the signal transduction of cholesterol synthesis is related to cancer invasion and why statins can suppress invasion and growth.

氧固醇结合蛋白相关蛋白（ORP）5的表达与胰腺癌的侵袭性和预后不良有关。ORP 5诱导了固醇反应元件结合蛋白（SREBP）2的表达，激活了固醇反应元件（SRE）的下游基因。利用SREBP 2抗体进行的染色体免疫沉淀（ChIP）显示HDAC 5是SREBP 2的下游基因之一。根据ORP 5的表达水平分析HMG-CoA还原酶抑制剂（他汀类药物）的作用。在强表达ORP 5的细胞中，侵袭率、生长以时间和剂量依赖性方式被抑制，但在弱表达ORP 5的细胞中效果较小，因此表明当侵袭和生长的潜力依赖于胆固醇合成途径时，其变得对HMG-CoA还原酶抑制剂敏感。此外，HDAC抑制剂tricostatin A（TSA），诱导表达的磷酸酶和张力蛋白同源物（PTEN），以及当ORP 5被抑制或细胞用他汀类药物处理。用他汀类药物和TSA治疗在高度表达ORP 5的细胞中显示出协同抗肿瘤作用。因此，在一些胰腺癌中，持续的ORP 5表达增强胆固醇合成途径，并且该信号转导通过HDAC 5表达调节PTEN。这是第一份关于胆固醇合成的信号转导如何与癌症侵袭相关以及他汀类药物为什么能抑制侵袭和生长的详细机制的报告。