MicroRNAs Cooperatively Inhibit a Network of Tumor Suppressor Genes to Promote Pancreatic Tumor Growth and Progression

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 146; no. 1; pp. 268 - 277.e18
• Main Authors: Frampton, Adam E, Castellano, Leandro, Colombo, Teresa, Giovannetti, Elisa, Krell, Jonathan, Jacob, Jimmy, Pellegrino, Loredana, Roca-Alonso, Laura, Funel, Niccola, Gall, Tamara M.H, De Giorgio, Alexander, Pinho, Filipa G, Fulci, Valerio, Britton, David J, Ahmad, Raida, Habib, Nagy A, Coombes, R. Charles, Harding, Victoria, Knösel, Thomas, Stebbing, Justin, Jiao, Long R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2014
• Subjects: Animals; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - physiology; Carcinoma, Pancreatic Ductal - genetics; Cell Line, Tumor; Cell Proliferation; Disease Progression; Endosomal Sorting Complexes Required for Transport - antagonists & inhibitors; Endosomal Sorting Complexes Required for Transport - physiology; Gastroenterology and Hepatology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - genetics; Genes, Tumor Suppressor - physiology; Humans; Immediate-Early Proteins - antagonists & inhibitors; Immediate-Early Proteins - physiology; Mice; MicroRNAs - genetics; MicroRNAs - physiology; miRNA−mRNA Interaction; Nedd4 Ubiquitin Protein Ligases; Oncogene; Pancreatic Cancer; Pancreatic Neoplasms - genetics; Prognosis; RNA, Messenger - genetics; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - physiology; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - physiology; Tumorigenesis; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - physiology; anti-miR; OS; Oncogene; mRNA; Pancreatic Cancer; antisense miRNA inhibitor; pre-miR; pancreatic ductal adenocarcinoma; negative control; precursor miRNA; PDAC; messenger RNA; NC; overall survival; miRNA−mRNA Interaction; miRNA; microRNA; Tumorigenesis
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2013.10.010

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.