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.

中文翻译：

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TGF-β1通过DDR1上调和I型胶原交联，促进肝癌细胞线性侵染体的形成。

转化生长因子-β1（TGF-β1）是慢性肝病中诱导纤维发生和肝细胞癌（HCC）发育的重要因素。TGF-β1在细胞和基质微环境水平上促进多效性修饰。据描述，TGF-β1可增强I型胶原蛋白及其相关交联酶赖氨酰氧化酶样2（LOXL2）的产生。另外，TGF-β1和I型胶原是侵入体的有效诱导剂。实际上，I型胶原纤维通过盘状蛋白结构域受体1（DDR1）诱导了活性线形体的形成。我们研究的目的是解决TGF-β1在胶原蛋白交联中的作用及其对肝癌细胞中线性线粒体形成的影响。我们首先报道了TGF-β1和I型胶原LOXL2的表达之间存在显着相关性，人类HCC中的DDR1和MT1-MMP。我们证明了在培养的HCC细胞中，TGF-β1促进了Smad4依赖性的DDR1与LOXL2的上调。此外，我们表明，LOXL2诱导的胶原蛋白交联增强了线性侵染小体的形成。总之，我们的数据表明，TGF-β1通过诱导剂（如胶原蛋白和LOXL2）以及癌细胞中线性侵染小体的DDR1和MT1-MMP等成分的表达，促进线性侵染小体的形成。同时，我们的数据揭示了DDR1表达的新的TGF-β1依赖性调节。我们的数据表明，TGF-β1通过诱导剂（如胶原蛋白和LOXL2）以及癌细胞中线性线粒体的DDR1和MT1-MMP等成分的表达，促进线性线粒体的形成。同时，我们的数据揭示了DDR1表达的新的TGF-β1依赖性调节。我们的数据表明，TGF-β1通过诱导剂（如胶原蛋白和LOXL2）以及癌细胞中线性线粒体的DDR1和MT1-MMP等成分的表达，促进线性线粒体的形成。同时，我们的数据揭示了DDR1表达的新的TGF-β1依赖性调节。