title: A Systematic Approach to Defining the microRNA Landscape in Metastasis.
abstract: The microRNA (miRNA) landscape changes during the progression of cancer. We defined a metastasis-associated miRNA landscape using a systematic approach. We profiled and validated miRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues. We identified an exclusive miRNA signature that is differentially expressed in metastases. Three of these miRNAs were identified as key drivers of an EMT-regulating network acting though a number of novel targets. These targets include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. The modulation of N-cadherin expression had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of the miRNAs defining the network was confirmed in an independent patient set as well as in a database of diverse malignancies derived from more than 6,000 patients. Our data define a novel metastasis-orchestrating network based on systematic hypothesis generation from metastasis tissues.
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Giridhar
authors.initials: G
authors.lastname: Mudduluru
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Centre for Biomedicine and Medical Technology Mannheim, Mannheim, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abba
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Batliner
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Centre for Biomedicine and Medical Technology Mannheim, Mannheim, Germany.
authors.forename: Nitin
authors.initials: N
authors.lastname: Patil
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Scharp
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Taral R
authors.initials: TR
authors.lastname: Lunavat
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Centre for Biomedicine and Medical Technology Mannheim, Mannheim, Germany.
authors.forename: Jörg Hendrik
authors.initials: JH
authors.lastname: Leupold
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Oleksiuk
authors.affiliation: Department of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dilafruz
authors.initials: D
authors.lastname: Juraeva
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim, Mannheim, Germany. Institute for Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Thiele
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim, Mannheim, Germany. Institute for Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rothley
authors.affiliation: Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Lautenberg Centre for Immunology and Cancer Research Institute for Medical Research Israel-Canada, The Hebrew University, Hadassah Medical School Jerusalem, Jerusalem, Israel.
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim, Mannheim, Germany. Institute for Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sleeman
authors.affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Centre for Biomedicine and Medical Technology Mannheim, Mannheim, Germany. heike.allgayer@medma.uni-heidelberg.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000556:secondary*; D016208:Databases, Factual; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D051858:Forkhead Transcription Factors; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D012016:Reference Values; D012097:Repressor Proteins / Q000235:genetics; D015203:Reproducibility of Results; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2; D000098563:Seven in Absentia Proteins
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; C106158:FOXN3 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; C544965:MIRN135 microRNA, human; C543800:MIRN210 microRNA, human; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins