Adam E Frampton1, Leandro Castellano2, Teresa Colombo3, Elisa Giovannetti4, Jonathan Krell5, Jimmy Jacob5, Loredana Pellegrino5, Laura Roca-Alonso5, Niccola Funel6, Tamara M H Gall1, Alexander De Giorgio5, Filipa G Pinho5, Valerio Fulci3, David J Britton7, Raida Ahmad8, Nagy A Habib1, R Charles Coombes5, Victoria Harding5, Thomas Knösel9, Justin Stebbing5, Long R Jiao10. 1. HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK. 2. 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. 3. Department of Cellular Biotechnology and Haematology, La Sapienza University, Rome, Italy. 4. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. 5. Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK. 6. Experimental and Molecular Oncology, Department of Surgery, University of Pisa, Pisa, Italy. 7. Proteome Sciences plc, King's College, London, UK. 8. Department of Pathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK. 9. Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany. 10. HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK. Electronic address: l.jiao@imperial.ac.uk.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: Christina Vorvis; Maria Hatziapostolou; Swapna Mahurkar-Joshi; Marina Koutsioumpa; Jennifer Williams; Timothy R Donahue; George A Poultsides; Guido Eibl; Dimitrios Iliopoulos Journal: Am J Physiol Gastrointest Liver Physiol Date: 2016-05-05 Impact factor: 4.052
Authors: Eva Karamitopoulou; Stefan Haemmig; Ulrich Baumgartner; Cornelia Schlup; Martin Wartenberg; Erik Vassella Journal: Mod Pathol Date: 2017-05-26 Impact factor: 7.842