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.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is one of the most devastating cancers with a 5-year relative survival rate of less than 5% [1]
We explored two miRNAs miR-199a-3p and miR-214-3p for their potential therapeutic role in the activation of pancreatic stellate cells (PSCs) and Pancreatic stellate cells (PSCs)-induced pro-tumorigenic effects in pancreatic cancer
Using in-situ hybridization technique, we confirmed that these miRs were overexpressed in pancreatic tumor stroma and subsequently their high expression was confirmed in patient-derived pancreatic cancer-associated fibroblasts (CAFs) and TGF-β-activated human PSCs (hPSCs)
Summary
Pancreatic ductal adenocarcinoma (PDA) is one of the most devastating cancers with a 5-year relative survival rate of less than 5% [1]. Clinical studies with a hedgehog inhibitor GDC-0449 failed to show the benefit in enhancing the anti-tumoral effect of gemcitabine [8]. Depletion of tumor stroma either by deleting myofibroblasts genetically or by inhibiting hedgehog pathway (using an inhibitor or with Shh deficient tumors) accelerated the tumor growth with reduced survival [5, 6]. These studies provoked the debate on the tumor-supportive or tumor-inhibitory action of cancer-associated fibroblasts (CAFs) [9], suggesting a mixed population of CAFs [10]. Silencing of CAF pro-tumorigenic activities, instead of their depletion, might be the right direction to develop anti-stromal therapies to treat pancreatic cancer [9]
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