title: Regulation of Melanoma Progression through the TCF4/miR-125b/NEDD9 Cascade.
abstract: Melanoma progression from a primary lesion to a distant metastasis is a complex process associated with genetic alterations, epigenetic modifications, and phenotypic switches. Elucidation of these phenomena may indicate how to interfere with this fatal disease. The role of microRNAs as key negative regulators of gene expression, controlling all cellular processes including cell migration and invasion, is now being recognized. Here, we used in silico analysis of microRNA expression profiles of primary and metastatic melanomas and functional experiments to show that microRNA-125b (miR-125b) is a determinant candidate of melanoma progression: (i) miR-125b is more strongly expressed in aggressive metastatic than primary melanomas, (ii) there is an inverse correlation between the amount of miR-125b and overall patient survival, (iii) invasion/migration potentials in vitro are inversely correlated with the amount of miR-125b in a series of human melanoma cell lines, and (iv) inhibition of miR-125b reduces migratory and invasive potentials without affecting cell proliferation in vitro. Furthermore, we show that neural precursor cell expressed developmentally down-regulated protein 9 (i.e., NEDD9) is a direct target of miR-125b and is involved in modulating melanoma cell migration and invasion. Also, transcription factor 4, associated with epithelial-mesenchymal transition and invasion, induces the transcription of miR-125b-1. In conclusion, the transcription factor 4/miR-125b/NEDD9 cascade promotes melanoma cell migration/invasion.
authors.affiliation: Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, Orsay, France; Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Rambow
authors.affiliation: Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, Orsay, France; Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bechadergue
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Flavie
authors.initials: F
authors.lastname: Luciani
authors.affiliation: Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, Orsay, France; Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Gros
authors.affiliation: Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, Orsay, France; Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Domingues
authors.affiliation: Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, Orsay, France; Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
authors.forename: Jacky
authors.initials: J
authors.lastname: Bonaventure
authors.affiliation: Plateforme de Bioinformatique, UMS AMMICA, Gustave-Roussy, Villejuif, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Meurice
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS UMR 3347, Orsay, France; Equipe Labellisée Ligue Contre le Cancer, Orsay, France. Electronic address: lionel.larue@curie.fr.
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D045744:Cell Line, Tumor / Q000166:cytology*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D012494:Sampling Studies; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D000096142:Cutaneous Malignant Melanoma
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C099942:NEDD9 protein, human; D010750:Phosphoproteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors