Study of proton pump inhibitors induced bile duct tumorigenesis.

Proton pump inhibitors (PPIs) are commonly used medications for the management of multiple gastrointestinal conditions. Currently, there are limited studies that focus on the adverse effect of long term usage of these drugs. Our aim was is to evaluate the role of PPIs in inducing cholangiocarcinoma. Our previous report showed dose dependent-effect of PPI on periampullary cancer in humans by designing a national population-based cohort study, based on Taiwan’s National health Insurance Research Database and the Taiwan Cancer Registry. Follow the result; we designed a study to establish an animal model. In the preliminary result, the tumorigenesis in bile duct of rat with long-term PPIs treatment was observed. However, the mechanism is unclear. In this present 3-year proposal, the main aims are 1) to evaluate the detailed effects of long-term treat with PPIs in rat, 2) to examine the mechanisms of long-term treat with PPIs induced tumorigenesis in rat, 3) correlated the mechanism to the clinical in human. To address aims of this proposal, in the aim 1 (first year): the organs and blood will be collected; the metabolites of PPIs in blood and bile duct of rat will be analyzed by pathological diagnosis and MALDI-TOF. The stool of rat will be collected for the gut microbiota analysis. In the aim 2 (second year), the microarray will be used to evaluate the mechanism of the tumorigenesis and the immunocytochemistry will be used to confirm the mechanism and biomarkers of cholangiocarcinoma. In the aim 3 (final year), confirm the mechanisms of proton pump inhibitors induce in human tissue from human cholangiocarcinoma patient. The tissue will buy the commercial tissue array and detection by immunohistochemistry and q-PCR.