miRNA-193b-5p Suppresses Pancreatic Cancer Cell Proliferation, Invasion, Epithelial Mesenchymal Transition, and Tumor Growth by Inhibiting eEF2K

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the US due to lack of effective targeted therapeutics and extremely poor prognosis. Objective: To investigate the role of miR-193b and related signaling mechanism in PDAC cell proliferation, invasion and tumor growth. Methods: Using PDAC cell lines we performed cell viability, colony formation, in vitro wound healing and matrigel invasion assays following transfection with miR-193b mimic or control-miR. To identify potential downstream targets of miR-193b we utilized miRNA-target prediction algorithms and investigate regulation of eukaryotic elongation factor-2 kinase (eEF2K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways and mediators of epithelial mesenchymal transition (EMT) The role of miR-193b in PDAC tumorigenesis was evaluated in in vivo tumor growth of Panc-1 xenograft model in nude mice. Results: We found that miR-193b is under expressed in PDAC cells compared to corresponding normal pancreatic epithelial cells and demonstrated that ectopic expression of miR-193b reduced cell proliferation, migration and invasion and EMT through downregulation of eEF2K signaling in PDAC cells. miR-193b expression led to increased expression of E-Cadherin and Claudin-1, while decreasing Snail and TCF8/ZEB1 expressions via eEF2K and MAPK/ERK axis. In vivo systemic injection of miR-193b using lipid-nanoparticles twice a week reduced tumor growth of Panc-1 xenografts and eEF2K expression in nude mice. Conclusions: Our findings suggest that miR-193b expression suppresses PDAC cell proliferation, migration, invasion and EMT through inhibition of eEF2K/MAPK-ERK oncogenic axis and that miR-193b-based RNA therapy might be an effective therapeutic strategy to control growth of PDAC.