MicroRNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer

Abstract 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 an...

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Bibliographic Details
Published in:Cancer letters 2016-04, Vol.373 (1), p.130-137
Main Authors: Fan, Pei, Liu, Li, Yin, Yefeng, Zhao, Zhefu, Zhang, Yiyao, Amponsah, Prince S, Xiao, Xi, Bauer, Nathalie, Abukiwan, Alia, Nwaeburu, Clifford C, Gladkich, Jury, Gao, Chao, Schemmer, Peter, Gross, Wolfgang, Herr, Ingrid
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Antimetabolites, Antineoplastic - pharmacology
Apoptosis
Binding Sites
Cancer therapies
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - enzymology
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Chemoresistance
Chemotherapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Deoxyribonucleic acid
DNA
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm - genetics
Enzymes
Epigenetics
Gene expression
Gene Expression Profiling - methods
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Hematology, Oncology and Palliative Medicine
Humans
Low density lipoprotein receptors
Lymphatic system
Metastasis
microRNA
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - enzymology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Patients
Ribonucleotide reductase
RNA Interference
Time Factors
Transfection
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Up-Regulation
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Summary:Abstract 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 M1 (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 non-malignant pancreas tissue. By microRNA expression profiling, we identified microRNA-101-3p as top-downregulated 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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2016.01.038