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

Praneeth R. Kuninty, Linda Bojmar, Vegard Tjomsland, Marie Larsson, Gert Storm, Arne Östman, Per Sandström, Jai Prakash

Research output: Contribution to journalArticleAcademicpeer-review

57 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)16396-16408
JournalOncotarget
Volume7
Issue number13
DOIs
Publication statusPublished - 2016

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