title: MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor.
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.
authors.affiliation: Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Twente, Netherlands.
authors.forename: Praneeth R
authors.initials: PR
authors.lastname: Kuninty
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Pediatric Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Bojmar
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Vegard
authors.initials: V
authors.lastname: Tjomsland
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Twente, Netherlands.|Department of Pharmaceutics, Utrecht University, Utrecht, Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Sandström
authors.affiliation: Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Twente, Netherlands.|Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska, Sweden.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
mesh_terms: D000070416:Antagomirs / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000070416:Antagomirs; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; C531408:mirn199 microRNA, human
keywords: cancer-associated fibroblasts; miRNA; pancreatic cancer; pancreatic stellate cells; stroma