title: Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin.
abstract: Hepatocellular carcinoma is associated with a high rate of intra-hepatic invasion that carries a poor prognosis. Meprin alpha (Mep1A) is a secreted metalloproteinase with many substrates relevant to cancer invasion. We found that Mep1A was a target of Reptin, a protein that is oncogenic in HCC. We studied Mep1A regulation by Reptin, its role in HCC, and whether it mediates Reptin oncogenic effects.MepA and Reptin expression was measured in human HCC by qRT-PCR and in cultured cells by PCR, western blot and enzymatic activity measurements. Cell growth was assessed by counting and MTS assay. Cell migration was measured in Boyden chambers and wound healing assays, and cell invasion in Boyden chambers.Silencing Reptin decreased Mep1A expression and activity, without affecting meprin β. Mep1A, but not meprin β, was overexpressed in a series of 242 human HCC (2.04 fold, p < 0.0001), and a high expression correlated with a poor prognosis. Mep1A and Reptin expressions were positively correlated (r = 0.39, p < 0.0001). Silencing Mep1A had little effect on cell proliferation, but decreased cell migration and invasion of HuH7 and Hep3B cells. Conversely, overexpression of Mep1A or addition of recombinant Mep1A increased migration and invasion. Finally, overexpression of Mep1A restored a normal cell migration in cells where Reptin was depleted.Mep1A is overexpressed in most HCC and induces HCC cell migration and invasion. Mep1A expression is regulated by Reptin, and Mep1A mediates Reptin-induced migration. Overall, we suggest that Mep1A may be a useful target in HCC.
authors.affiliation: University Bordeaux, INSERM, U1053, BordeAux Research in Translational Oncology, BaRITOn, Bordeaux, France.
authors.forename: Osman
authors.initials: O
authors.lastname: Breig
authors.affiliation: University Bordeaux, INSERM, U1053, BordeAux Research in Translational Oncology, BaRITOn, Bordeaux, France.
authors.forename: Maïlyn
authors.initials: M
authors.lastname: Yates
authors.affiliation: University Bordeaux, INSERM, U1053, BordeAux Research in Translational Oncology, BaRITOn, Bordeaux, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Neaud
authors.affiliation: Inserm, U1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot, Université Paris Descartes, Université Paris 13, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: University Bordeaux, INSERM, U1053, BordeAux Research in Translational Oncology, BaRITOn, Bordeaux, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Grigoletto
authors.affiliation: SIRIC BRIO, Bordeaux, France.
authors.forename: Carlo
authors.initials: C
authors.lastname: Lucchesi
authors.affiliation: Unit for Degradomics of the Protease Web, University of Kiel, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Prox
authors.affiliation: Inserm, U1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot, Université Paris Descartes, Université Paris 13, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: Unit for Degradomics of the Protease Web, University of Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.affiliation: University Bordeaux, INSERM, U1053, BordeAux Research in Translational Oncology, BaRITOn, Bordeaux, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D008666:Metalloendopeptidases; C053833:meprin A; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C122079:RUVBL2 protein, human
keywords: RUVBL2; prognosis; proteolysis