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MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor
Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, The Netherlands.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 13, 16396-16408 p.Article in journal (Refereed) Published
Abstract [en]

Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. Although depletion of tumor stroma is debatable, attenuation of PSC activity is still an interesting strategy to treat pancreatic cancer. 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 as well as in TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a or miR-214 using their hairpin inhibitors in hPSCs significantly inhibited their TGFβ-induced differentiation (gene and protein levels of α-SMA, Collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs were prepared, which attained smaller size when hPSCs were transfected with anti-miR-199a or -214 than those transfected with control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell proliferation and endothelial cell tube formation, but these effects were abrogated when hPSCs were 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 PSCs in pancreatic cancer.

Place, publisher, year, edition, pages
Impact press, 2016. Vol. 7, no 13, 16396-16408 p.
National Category
Cancer and Oncology Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-122828DOI: 10.18632/oncotarget.7651ISI: 000375692900085OAI: oai:DiVA.org:liu-122828DiVA: diva2:874170
Note

Funding agencies: Swedish Research Council, Stockholm, Sweden [K7/60501283]

Vid tiden för disputationen förelåg publikationen endast som manuskript

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2016-06-09
In thesis
1. Metastatic Mechanisms in Malignant Tumors
Open this publication in new window or tab >>Metastatic Mechanisms in Malignant Tumors
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In  breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 91 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1487
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-122830 (URN)978-91-7685-934-6 (print) (ISBN)
Public defence
2015-12-18, Hasselqvistsalen, Ingång 76, Hus 511, Campus US, Linköping, 09:00 (Swedish)
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Supervisors
Note

The ISBN 987-91-7685-934-6 in the printed version is incorrect. The correct ISBN is  978-91-7685-934-6.

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2015-12-18Bibliographically approved

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Bojmar, LindaTjomsland, VegardLarsson, MarieSandström, Per
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Division of Clinical SciencesFaculty of Medicine and Health SciencesDivision of Microbiology and Molecular MedicineDepartment of Surgery in Linköping
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OncoTarget
Cancer and OncologyCell and Molecular BiologyMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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