TGF-β1 promotes linear invadosome formation in hepatocellular carcinoma cells, through DDR1 up-regulation and collagen I cross-linking

• Published in: European journal of cell biology Vol. 95; no. 11; pp. 503 - 512
• Main Authors: Ezzoukhry, Zakaria, Henriet, Elodie, Piquet, Léo, Boyé, Kevin, Bioulac-Sage, Paulette, Balabaud, Charles, Couchy, Gabrielle, Zucman-Rossi, Jessica, Moreau, Violaine, Saltel, Frédéric
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.11.2016
• Subjects: Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Cross-linking; Discoidin domain receptor 1; Discoidin Domain Receptor 1 - biosynthesis; Discoidin Domain Receptor 1 - genetics; Gene Expression Regulation, Neoplastic; Humans; Invadosomes; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lysyl oxidase-like2; Neoplasm Invasiveness; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; TGF-β1; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Up-Regulation; DDR1; IGF-I; RTK; Lysyl oxidase-like2; mRNA; LOXL2; Discoidin domain receptor 1; MT1-MMP; CAFs; PI3K; Cross-linking; miRNA; Cdc42; Invadosomes; EGF; VEGF; HCC; EMT; ECM; F-actin; LOX; MMP-2; Collagen; TGF-β1; ERK
• ISSN: 0171-9335; 1618-1298
• DOI: 10.1016/j.ejcb.2016.09.003

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.