title: MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression.
abstract: OBJECTIVE
  There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes.
  
  
  METHODS
  We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA-mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We used this information to identify miRNAs that contribute most to tumorigenesis.
  
  
  RESULTS
  We identified 3 miRNAs (MIR21, MIR23A, and MIR27A) that acted as cooperative repressors of a network of tumor suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of MIR21, MIR23A, and MIR27A had synergistic effects in reducing proliferation of PDAC cells in culture and growth of xenograft tumors in mice. The level of inhibition was greater than that of inhibition of MIR21 alone. In 91 PDAC samples from patients, high levels of a combination of MIR21, MIR23A, and MIR27A were associated with shorter survival times after surgical resection.
  
  
  CONCLUSIONS
  In an integrated data analysis, we identified functional miRNA-mRNA interactions that contribute to growth of PDACs. These findings indicate that miRNAs act together to promote tumor progression; therapeutic strategies might require inhibition of several miRNAs.
authors.affiliation: HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Frampton
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK. Electronic address: l.castellano@imperial.ac.uk.
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
authors.affiliation: Department of Cellular Biotechnology and Haematology, La Sapienza University, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Colombo
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krell
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Jacob
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Loredana
authors.initials: L
authors.lastname: Pellegrino
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Roca-Alonso
authors.affiliation: Experimental and Molecular Oncology, Department of Surgery, University of Pisa, Pisa, Italy.
authors.forename: Niccola
authors.initials: N
authors.lastname: Funel
authors.affiliation: HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK.
authors.forename: Tamara M H
authors.initials: TM
authors.lastname: Gall
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: De Giorgio
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Filipa G
authors.initials: FG
authors.lastname: Pinho
authors.affiliation: Department of Cellular Biotechnology and Haematology, La Sapienza University, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Fulci
authors.affiliation: Proteome Sciences plc, King's College, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Britton
authors.affiliation: Department of Pathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Raida
authors.initials: R
authors.lastname: Ahmad
authors.affiliation: HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK.
authors.forename: Nagy A
authors.initials: NA
authors.lastname: Habib
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Harding
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knösel
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK. Electronic address: l.jiao@imperial.ac.uk.
authors.forename: Long R
authors.initials: LR
authors.lastname: Jiao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D000075702:Nedd4 Ubiquitin Protein Ligases; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D017874:Immediate-Early Proteins; C524940:MIRN21 microRNA, human; C552430:MIRN23a microRNA, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: NC; OS; Oncogene; PDAC; Pancreatic Cancer; Tumorigenesis; anti-miR; antisense miRNA inhibitor; mRNA; messenger RNA; miRNA; miRNA−mRNA Interaction; microRNA; negative control; overall survival; pancreatic ductal adenocarcinoma; pre-miR; precursor miRNA