title: PEA3 transcription factors are downstream effectors of Met signaling involved in migration and invasiveness of Met-addicted tumor cells.
abstract: Various solid tumors including lung or gastric carcinomas display aberrant activation of the Met receptor which correlates with aggressive phenotypes and poor prognosis. Although downstream signaling of Met is well described, its integration at the transcriptional level is poorly understood. We demonstrate here that in cancer cells harboring met gene amplification, inhibition of Met activity with tyrosine kinase inhibitors or specific siRNA drastically decreased expression of ETV1, ETV4 and ETV5, three transcription factors constituting the PEA3 subgroup of the ETS family, while expression of the other members of the family were less or not affected. Similar link between Met activity and PEA3 factors expression was found in lung cancer cells displaying resistance to EGFR targeted therapy involving met gene amplification. Using silencing experiments, we demonstrate that the PEA3 factors are required for efficient migration and invasion mediated by Met, while other biological responses such as proliferation or unanchored growth remain unaffected. PEA3 overexpression or silencing revealed that they participated in the regulation of the MMP2 target gene involved in extracellular matrix remodeling. Our results demonstrated that PEA3-subgroup transcription factors are key players of the Met signaling integration involved in regulation of migration and invasiveness.
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: Zoulika
authors.initials: Z
authors.lastname: Kherrouche
authors.affiliation: CNRS USR 3078, Institut de Recherche Interdisciplinaire, Université de Lille, Villeneuve d'Ascq 59658, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Monte
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France; BioImaging Center Lille Nord de France, Lille 59021, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Werkmeister
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Stoven
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: De Launoit
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France; Thoracic Oncology Department, Lille University Hospital, Université de Lille, France.
authors.forename: Alexis B
authors.initials: AB
authors.lastname: Cortot
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France. Electronic address: david.tulasne@ibl.cnrs.fr.
authors.forename: David
authors.initials: D
authors.lastname: Tulasne
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Chotteau-Lelievre
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; C065788:transcription factor PEA3; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: EGFR; ETS; Lung tumorigenesis; Met; Migration; PEA3; Receptor tyrosine kinase; Transcription factor