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

氧固醇结合蛋白相关蛋白(ORP)5的表达与胰腺癌的侵袭和预后不良有关。ORP5诱导固醇反应元件结合蛋白(SREBP)2的表达，并激活固醇反应元件(SRE)下游基因。用SREBP2抗体进行的染色体免疫沉淀(CHIP)显示，HDAC5是SREBP2的下游基因之一。根据ORP5的表达水平分析HMG-CoA还原酶抑制剂(他汀类)的作用。高表达ORP5的细胞侵袭率和生长受到时间和剂量依赖性的抑制，而弱表达ORP5的细胞侵袭率和生长受到抑制，提示当细胞的侵袭和生长依赖于胆固醇合成途径时，它对HMG-CoA还原酶抑制剂变得敏感。此外，当ORP5被抑制或他汀类药物处理细胞时，HDAC抑制剂Tricostatin A(TSA)也能诱导PTEN的表达。在高表达ORP5的细胞中，他汀类药物和TSA治疗显示出协同的抗肿瘤作用。因此，在一些胰腺癌中，持续的ORP5表达增强了胆固醇的合成途径，该信号转导通过HDAC5的表达来调节PTEN。这是关于胆固醇合成的信号转导如何与癌症侵袭相关的详细机制的第一份报告，以及为什么他汀类药物可以抑制侵袭和生长。

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.