title: TGF-β1 promotes linear invadosome formation in hepatocellular carcinoma cells, through DDR1 up-regulation and collagen I cross-linking.
abstract: Transforming growth factor-β1 (TGF-β1) is an important player in chronic liver diseases inducing fibrogenesis and hepatocellular carcinoma (HCC) development. TGF-β1 promotes pleiotropic modifications at the cellular and matrix microenvironment levels. TGF-β1 was described to enhance production of type I collagen and its associated cross-linking enzyme, the lysyl oxidase-like2 (LOXL2). In addition, TGF-β1 and type I collagen are potent inducers of invadosomes. Indeed, type I collagen fibers induce the formation of active linear invadosomes through the discoidin domain receptor 1 (DDR1). The goal of our study was to address the role of TGF-β1 in collagen cross-linking and its impact on the formation of linear invadosomes in liver cancer cells. We first report a significant correlation between expressions of TGF-β1, and type I collagen, LOXL2, DDR1 and MT1-MMP in human HCCs. We demonstrate that TGF-β1 promotes a Smad4-dependent up-regulation of DDR1, together with LOXL2, in cultured HCC cells. Moreover, we show that LOXL2-induced collagen cross-linking enhances linear invadosome formation. Altogether, our data demonstrate that TGF-β1 favors linear invadosome formation through the expressions of both the inducers, such as collagen and LOXL2, and the components such as DDR1 and MT1-MMP of linear invadosomes in cancer cells. Meanwhile, our data uncover a new TGF-β1-dependent regulation of DDR1 expression.
authors.affiliation: Mohammed 6 University of health Sciences (UM6SS), Faculty of Medicine, National Laboratory of Reference, Casablanca, Morocco.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Ezzoukhry
authors.affiliation: INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Univ. Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Henriet
authors.affiliation: INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Univ. Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
authors.forename: Léo
authors.initials: L
authors.lastname: Piquet
authors.affiliation: INSERM, U1029 Angiogenesis and tumor microenvironment laboratory, F-33000 Bordeaux, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Boyé
authors.affiliation: INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Univ. Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Univ. Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.affiliation: INSERM, UMR1162, Génomique Fonctionnelle des Tumeurs Solides, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France; Université Paris Diderot, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: INSERM, UMR1162, Génomique Fonctionnelle des Tumeurs Solides, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France; Université Paris Diderot, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Univ. Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France.
authors.forename: Violaine
authors.initials: V
authors.lastname: Moreau
authors.affiliation: INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Univ. Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France. Electronic address: frederic.saltel@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saltel
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000070819:Discoidin Domain Receptor 1 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D009363:Neoplasm Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1
keywords: Collagen; Cross-linking; Discoidin domain receptor 1; Invadosomes; Lysyl oxidase-like2; TGF-β1