MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor

Abstract

// Praneeth R. Kuninty 1 , Linda Bojmar 2, 3 , Vegard Tjomsland 2, 4 , Marie Larsson 2 , Gert Storm 1, 5 , Arne Östman 6 , Per Sandström 2 , Jai Prakash 1, 6 1 Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Twente, Netherlands 2 Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden 3 Department of Pediatric Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA 4 Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway 5 Department of Pharmaceutics, Utrecht University, Utrecht, Netherlands 6 Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska, Sweden Correspondence to: Jai Prakash, e-mail: j.prakash@utwente.nl Keywords: pancreatic cancer, pancreatic stellate cells, miRNA, stroma, cancer-associated fibroblasts Received: September 15, 2015      Accepted: January 29, 2016      Published: February 24, 2016 ABSTRACT Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs and TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a/-214 using hairpin inhibitors significantly inhibited TGFβ-induced differentiation markers (e.g. α-SMA, collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs attained smaller size with hPSCs transfected with anti-miR-199a/-214 compared to control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell growth and endothelial cell tube formation. Interestingly, these inductions were abrogated in hPSCs transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in pancreatic cancer.