title: miR-211 modulates gemcitabine activity through downregulation of ribonucleotide reductase and inhibits the invasive behavior of pancreatic cancer cells.
abstract: Only a subset of radically-resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from gemcitabine-based chemotherapy, thus the identification of novel prognostic factors is essential. In a high-throughput, microRNA (miRNA) array, miR-211 emerged as the best discriminating miRNA, with high expression associated with long survival. Here, we further explored the biological role of miRNA-211 in gemcitabine activity in the human PDAC cells (SUIT-2) subclones SUIT2-007 and SUIT2-028. Our results showed that miR-211 was expressed differentially in PDAC cells characterized by differential metastatic capability. In particular, S2-028 with lower metastatic ability had a higher expression of miR-211, compared to the S2-007 with higher metastatic capacity. Enforced expression of miR-211 via pre-miR-211 significantly reduced cell migration and invasion (e.g., 40% reduction of invasion of SUIT2 cells, compared to control; p<.05). Moreover, we demonstrated that induction of the miR-211 expression in the cells increased the sensitivity to gemcitabine and reduced the expression of its target ribonucleotide reductase subunit 2 (RRM2). In conclusion, miR-211 functional analyses suggested the role of RRM2 as a target of miR-211 in the modulation of gemcitabine sensitivity. Moreover, inhibition of cell migration and invasion might explain the less aggressive behavior of pancreatic cancer cells with higher expression levels of miR-211.
authors.affiliation: a Department of Medical Oncology , VU University Medical Center , Amsterdam , Amsterdam , The Netherlands.
authors.forename: Mina
authors.initials: M
authors.lastname: Maftouh
authors.forename: Amir
authors.initials: A
authors.lastname: Avan
authors.forename: Niccola
authors.initials: N
authors.lastname: Funel
authors.forename: Adam E
authors.initials: AE
authors.lastname: Frampton
authors.forename: Hamid
authors.initials: H
authors.lastname: Fiuji
authors.forename: Serena
authors.initials: S
authors.lastname: Pelliccioni
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
authors.forename: Valentina
authors.initials: V
authors.lastname: Galla
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000473:pathology*; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C549405:MIRN211 microRNA, human; D035683:MicroRNAs; D003841:Deoxycytidine; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine
keywords: Pancreatic ductal adenocarcinoma (PDAC); RRM2; gemcitabine; invasive behavior; miR-211