Inhibition of miR-21 regulates mutant KRAS effector pathways and intercepts pancreatic ductal adenocarcinoma development [miRNA]

We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted pro-tumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. miR-21 inhibition downregulated MAPK, mTOR and actin cytoskeleton pathways downstream of KRAS activation in tumor cells. In vivo miR-21 inhibition improved survival in established PDA, while early systemic miR-21 inhibition intercepted premalignant progression. TaqMan OpenArray Rodent MicroRNA Panel. We conducted a comprehensive miRNA profiling study of multiple PanIN stages and PDA using KPC mice. We performed microdissections on increasing grades of PanINs from sections of KPC pancreata followed by a miRNA microarray analysis utilizing the Taqman OpenArray platform to quantify the levels of 750 known murine miRNAs.