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CHARACTERIZING THE ROLE OF PANCREATIC STELLATE CELLS IN THE TRANSITION OF CHRONIC PANCREATITIS TO PANCREATIC CANCERBackground- Chronic pancreatitis (CP) and pancreatic cancer are two diseases that share a mutual histological feature known as fibrosis produced by pancreatic stellate cells (PaSCs). In response to pancreatic inflammation, PaSCs are activated from quiescent phenotype into myofibroblast-like cells, which express extracellular matrix components. PaSCs are also known to facilitate the migration and invasion of pancreatic cancer cells, which are accompanied by increased matrix metalloprotease (MMP) production and epithelial-to mesenchymal transition (EMT). NADPH oxidase (Nox) is a family of enzymes that catalyze the transfer of an electron from NAD(P)H to oxygen to generate superoxide or hydrogen peroxide. Because Nox1 is expressed in PaSCs, the objective of this study was to assess the extent to which Nox1 in PaSCs facilitates the migration and invasion of pancreatic cancer cells by regulating the expression of MMP and genes involved in EMT. Results/Discussion-We found that the lack of Nox1 lowers the expression of MMP-9 mRNA and the EMT-induced gene Snail in PaSCs. Further studies need to be done in PaSCs from mice with CP and CP-associated oncogenic KRas-driven pancreatic cancer.
PANCREATIC STELLATE NOX 1-DERIVED ROS FACILIATE INVASION OF PANCREATIC CANCER CELLS THROUGH MATRIX METALLOPROTEINASE 9Pancreatic ductal adenocarcinoma (PDAC) is a type of exocrine cancer that accounts for almost all cases of pancreatic cancer. Many studies show that chronic pancreatitis (CP), a long-term inflammation of the pancreas, is considered as the greatest risk factor for developing pancreatic cancer. We found that reactive oxygen species (ROS) generated by NADPH oxidase 1 (Nox1) in pancreatic stellate cells (PaSCs) mediate the fibrogenic process in CP. PaSCs are a class of pancreatic cells that, in the stroma surrounding pancreatic cancer cells, are known to facilitate cancer cell invasion. We found that the lack of Nox1 in PaSCs decreased the invasion of three different pancreatic cell lines using two approaches: transwell cell invasion and culture wound closure assays. The lack of Nox1 also decreased the expression of matrix metalloproteinase 9, which is an enzyme that breaks down the basal lamina, facilitating cell invasion. Using mass spectroscopy, we will assess the extent to which the lack of Nox1 in PaSCs affects the production of pro-migratory and pro-invasive proteins using mass spectroscopy. These results implicate Nox1 inhibitors as a potential therapeutic drug to impede the progression of CP to PDAC.