PEA3 transcription factors are downstream effectors of Met signaling involved in migration and invasiveness of Met-addicted tumor cells

• Published in: Molecular oncology 2015-11, Vol.9 (9), p.1852-1867
• Main Authors: Kherrouche, Zoulika, Monte, Didier, Werkmeister, Elisabeth, Stoven, Luc, De Launoit, Yvan, Cortot, Alexis B., Tulasne, David, Chotteau-Lelievre, Anne
• Format: Article
• Language: English
• Subjects: c-Met protein; Cell adhesion & migration; Cell Line, Tumor; Cell Movement; Clinical trials; Deoxyribonucleic acid; DNA; EGFR; Epidermal growth factor receptors; ETS; Extracellular matrix; Gastric cancer; Gelatinase A; Gene Amplification; Gene Expression Regulation, Neoplastic; Growth factors; Humans; Integration; Invasiveness; Kinases; Life Sciences; Ligands; Lung cancer; Lung carcinoma; Lung tumorigenesis; Met; MET protein; Metastasis; Migration; Morphogenesis; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; PEA3; Phenotypes; Protein-tyrosine kinase; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Receptor tyrosine kinase; Signal Transduction; siRNA; Solid tumors; Transcription factor; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor cells; Tumorigenesis; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2015.07.001

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. •Integration of the Met receptor signaling at the transcriptional level is poorly understood.•In cancer cells harboring met gene amplification, expression of ETV1, 4 and 5 is dependent of the receptor activity.•PEA3 factors are required for efficient migration and invasion mediated by Met, while other responses remain unaffected.•The three PEA3 factors are key players of the Met signaling integration involved in regulation of migration and invasiveness.