Journal
CANCER LETTERS
Volume 373, Issue 1, Pages 130-137Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.01.038
Keywords
Epigenetics; microRNA; Chemoresistance
Categories
Funding
- Heidelberger Stiftung Chirurgie
- Federal Ministry of Education and Research [BMBF 01GS08114, BMBF 031A213]
- Biomaterial Bank Heidelberg/BMBH [BMBF 01EY1101]
- German Cancer Aid (Deutsche Krebshilfe) [109362, 111299]
- Stiftung fur Krebs and Scharlachforschung
- Dietmar Hopp-Stiftung and Hanns A. Pielenz Stiftung
- China Scholarship Council [201308080097]
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Pancreatic ductal adenocarcinoma (PDA) is among the most lethal malignancies and resistance to chemotherapy prevents the therapeutic outcome. MicroRNAs provide a novel therapeutic strategy. Here, the established and primary human PDA cell lines PANC-1, AsPC-1, MIA-PaCa2, AsanPaCa, BxPC-3 and three gemcitabine-resistant subclones were examined. A gene expression profiling revealed that the ribonucleotide reductase Ml (RRM1) was upregulated in gemcitabine-resistant cells, which was confirmed by qRT-PCR, Western blot analysis and immunostaining. Inhibition of RRM1 by lipotransfection of siRNA reduced its expression and reversed gemcitabine resistance. The expression of RRM1 correlated to gemcitabine resistance in vitro and was higher in malignant patient pancreas tissue compared to nonmalignant pancreas tissue. By microRNA expression profiling, we identified microRNA-101-3p as topdownregulated candidate. Lipotransfection of microRNA-101-3p mimics inhibited the expression of RRM1, reduced the luciferase activity of its 3'UTR and sensitized for gemcitabine-induced cytotoxicity. These results underline the relevance of microRNA-101-3p-driven regulation of RRM1 in drug resistance and suggest the co-delivery of microRNA-101-3p and gemcitabine for more effective therapy outcome. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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