title: Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2.
abstract: Prostate cancer (PCa) is one of the major public health problems in Western countries. Recently, the TMPRSS2:ERG gene fusion, which results in the aberrant expression of the transcription factor ERG, has been shown to be the most common gene rearrangement in PCa. Previous studies have determined the contributions of this fusion in PCa disease initiation and/or progression in vitro and in vivo. In this study on TMPRSS2:ERG regulation in PCa, we used an androgen receptor and TMPRSS2:ERG fusion double-negative PCa cell model: PC3c. In three cell clones with different TMPRSS2:ERG expression levels, ectopic expression of the fusion resulted in significant induction of cell migration and invasion in a dose-dependent manner. In agreement with this phenotype, high-throughput microarray analysis revealed that a set of genes, functionally associated with cell motility and invasiveness, were deregulated in a dose-dependent manner in TMPRSS2:ERG-expressing cells. Importantly, we identified increased MMP9 (Metalloproteinase 9) and PLXNA2 (Plexin A2) expression in TMPRSS2:ERG-positive PCa samples, and their expression levels were significantly correlated with ERG expression in a PCa cohort. In line with these findings, there was evidence that TMPRSS2:ERG directly and positively regulates MMP9 and PLXNA2 expression in PC3c cells. Moreover, PLXNA2 upregulation contributed to TMPRSS2:ERG-mediated enhancements of PC3c cell migration and invasion. Furthermore, and importantly, PLXNA2 expression was upregulated in metastatic PCa tumors compared with localized primary PCa tumors. This study provides novel insights into the role of the TMPRSS2:ERG fusion in PCa metastasis.
authors.affiliation: 1] Institut de Biologie de Lille, CNRS UMR8161, Lille, France [2] Institut Pasteur de Lille/IFR142, Lille, France [3] Université de Lille Nord de France, Lille, France [4] Faculté de Médecine Henri Warembourg, Université du Droit et de la Santé Lille II, Lille, France.
authors.forename: T V
authors.initials: TV
authors.lastname: Tian
authors.affiliation: 1] Institut de Biologie de Lille, CNRS UMR8161, Lille, France [2] Institut Pasteur de Lille/IFR142, Lille, France [3] Université de Lille Nord de France, Lille, France.
authors.forename: N
authors.initials: N
authors.lastname: Tomavo
authors.affiliation: 1] Institut Pasteur de Lille/IFR142, Lille, France [2] Université de Lille Nord de France, Lille, France [3] Centre d'Infection et d'Immunité de Lille (CIIL), INSERM U1019, CNRS UMR8204, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Huot
authors.affiliation: 1] Institut de Biologie de Lille, CNRS UMR8161, Lille, France [2] Institut Pasteur de Lille/IFR142, Lille, France [3] Université de Lille Nord de France, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Flourens
authors.affiliation: INSERM U1033, Lyon, France.
authors.forename: E
authors.initials: E
authors.lastname: Bonnelye
authors.affiliation: 1] Institut de Biologie de Lille, CNRS UMR8161, Lille, France [2] Institut Pasteur de Lille/IFR142, Lille, France [3] Université de Lille Nord de France, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Flajollet
authors.affiliation: 1] Institut Pasteur de Lille/IFR142, Lille, France [2] Université de Lille Nord de France, Lille, France [3] Centre d'Infection et d'Immunité de Lille (CIIL), INSERM U1019, CNRS UMR8204, Lille, France.
authors.forename: D
authors.initials: D
authors.lastname: Hot
authors.affiliation: 1] Université de Lille Nord de France, Lille, France [2] Faculté de Médecine Henri Warembourg, Université du Droit et de la Santé Lille II, Lille, France [3] Centre hospitalier régional et universitaire de Lille, Institut de Pathologie, Lille, France.
authors.forename: X
authors.initials: X
authors.lastname: Leroy
authors.affiliation: 1] Institut de Biologie de Lille, CNRS UMR8161, Lille, France [2] Institut Pasteur de Lille/IFR142, Lille, France [3] Université de Lille Nord de France, Lille, France.
authors.forename: Y
authors.initials: Y
authors.lastname: de Launoit
authors.affiliation: 1] Institut de Biologie de Lille, CNRS UMR8161, Lille, France [2] Institut Pasteur de Lille/IFR142, Lille, France [3] Université de Lille Nord de France, Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Duterque-Coquillaud
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; C515995:PLXNA2 protein, human; D011956:Receptors, Cell Surface; C515553:TMPRSS2-ERG fusion protein, human; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9