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

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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.