Evaluation of the antitumorigenic roles of miR-122 in pancreatic cancer

PROJECT SUMMARY The fundamental roles of microRNAs (miRs) in tumor biology and drug resistance are increasingly being recognized. The objective of this application is to study the tumor suppressor role of miR-122, a liver-enriched miR, in pancreatic cancer. Our published research demonstrates that the epigenetic reprogramming of silenced miRs in pancreatic cancer can inhibit tumorigenicity and epithelial-mesenchymal transition (EMT)- induced chemoresistance. In our preliminary studies, we found that among the miRs silenced in pancreatic ductal adenocarcinoma (PDAC), miR-122 exhibits superior potency in suppressing tumorigenicity and PDAC- associated EMT in vitro. Our hypothesis in this application is that miR-122 is a tumor suppressor in PDAC and that the loss or gain of miR-122 function in genetically modified mouse models would have significant effects on pancreatic tumorigenicity and chemoresistance. In Aim 1, we will study the role of miR-122 in mouse pancreatic tumorigenesis. This aim is supported by our preliminary studies demonstrating that miR-122 expression is downregulated in human PDAC tissues and that miR-122 exerts anti-tumorigenic effects in human PDAC cell lines and in orthotopic and syngeneic mouse models of PDAC. By evaluating mice with global and pancreas-specific deletion of miR-122 and by transgenically restoring miR-122 expression in a Kras-p53 mutant mouse model of pancreatic cancer (KPC), we will investigate the impact of miR-122 on the initiation and progression of mouse PDAC. In Aim 2, we will investigate the mechanism by which miR-122 inhibits EMT in pancreatic cancer. Since EMT enhances drug resistance and miR-122 inhibits pro-EMT signals, we will study the effect of miR-122 on EMT-driven genes and pathways in pancreatic cancer; this approach is supported by our preliminary studies predicting that miR-122 inhibits the expression of the putative EMT genes SLC39A9 and FoxP2 through RNA interference. Using biochemical approaches and transcriptomic and metabolomic studies, we will reveal the role of miR-122 and its mRNA targets in EMT and also determine the metabolic and transcriptomic landscapes of miR-122-regulated EMT processes in PDAC. The successful completion of both of these aims would provide convincing evidence of how miR-122 controls tumorigenicity and EMT plasticity in pancreatic cancer. Thus, these studies will break new ground in pancreatic cancer research and may have a translational impact on improving therapeutic outcomes for patients.