title: 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 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.
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Pei
authors.initials: P
authors.lastname: Fan
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Yefeng
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Zhefu
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Yiyao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Prince S
authors.initials: PS
authors.lastname: Amponsah
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Xi
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bauer
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Alia
authors.initials: A
authors.lastname: Abukiwan
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Nwaeburu
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jury
authors.initials: J
authors.lastname: Gladkich
authors.affiliation: Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gross
authors.affiliation: Molecular OncoSurgery, University of Heidelberg, Heidelberg, Germany; Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address: i.herr@uni-heidelberg.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001665:Binding Sites; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D012262:Ribonucleoside Diphosphate Reductase; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000093542:Gemcitabine
chemical_list: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine
keywords: Chemoresistance; Epigenetics; microRNA