title: Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β-SMAD3 pathway in non-small cell lung adenocarcinoma.
abstract: Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.
authors.affiliation: Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy;
authors.forename: Maurizio
authors.initials: M
authors.lastname: Risolino
authors.affiliation: Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), 20139 Milan, Italy;
authors.forename: Nadia
authors.initials: N
authors.lastname: Mandia
authors.affiliation: Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy;
authors.forename: Francescopaolo
authors.initials: F
authors.lastname: Iavarone
authors.affiliation: Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), 20139 Milan, Italy;
authors.forename: Leila
authors.initials: L
authors.lastname: Dardaei
authors.affiliation: Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), 20139 Milan, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Longobardi
authors.affiliation: Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy;
authors.forename: Serena
authors.initials: S
authors.lastname: Fernandez
authors.affiliation: Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Talotta
authors.affiliation: Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), 20139 Milan, Italy; Department of Medicine, Surgery, and Dentistry, University of Milan, 20122 Milan, Italy;
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bianchi
authors.affiliation: Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), 20139 Milan, Italy;
authors.forename: Federica
authors.initials: F
authors.lastname: Pisati
authors.affiliation: Department of Medicine, Surgery, and Dentistry, University of Milan, 20122 Milan, Italy;
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Spaggiari
authors.affiliation: Neuroscience Center, Neurological Institute (Edinger Institut), 60528 Frankfurt, Germany; and.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Neuroscience Center, Neurological Institute (Edinger Institut), 60528 Frankfurt, Germany; and.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Neuroscience Center, Neurological Institute (Edinger Institut), 60528 Frankfurt, Germany; and.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Schulte
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico SDN (IRCCS SDN), 80142 Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Incoronato
authors.affiliation: Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), 20139 Milan, Italy; Department of Medicine, Surgery, and Dentistry, University of Milan, 20122 Milan, Italy;
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), 20139 Milan, Italy; francesco.blasi@ifom.eu pasquale.verde@igb.cnr.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.affiliation: Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; Istituto di Ricovero e Cura a Carattere Scientifico SDN (IRCCS SDN), 80142 Naples, Italy francesco.blasi@ifom.eu pasquale.verde@igb.cnr.it.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Verde
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007438:Introns / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010447:Peptide Hydrolases / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D000099169:Fos-Related Antigen 1
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D010447:Peptide Hydrolases; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D051900:Smad3 Protein; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D000099169:Fos-Related Antigen 1; C106682:PKNOX1 protein, human; C497790:SMAD3 protein, human; C083400:PBX1 protein, human
keywords: PTGFβ; TALE proteins