Title:miRNA-193b-5p Suppresses Pancreatic Cancer Cell Proliferation, Invasion, Epithelial
Mesenchymal Transition, and Tumor Growth by Inhibiting eEF2K
Volume: 22
Issue: 14
Author(s): Nilgun Gurbuz, Nermin Kahraman, Hafize Elif Sonmez, Hamada Ahmed Mokhlis, Pinar Aslan Kosar and Bulent Ozpolat*
Affiliation:
- Department of Experimental Therapeutics,
The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Keywords:
Pancreatic cancer, miRNA, miR-193b, EMT, eEF2K, proliferation, metastasis.
Abstract:
Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the US
due to the lack of effective targeted therapeutics and extremely poor prognosis.
Objective: The study aims to investigate the role of miR-193b and related signaling mechanisms 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 investigated the 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, 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 the growth of PDAC.