Galectin-1 Controls the Proliferation and Migration of Liver Sinusoidal Endothelial Cells and Their Interaction With Hepatocarcinoma Cells

Galectin‐1 (Gal1), a β‐galactoside‐binding protein elevated in hepatocellular carcinoma (HCC), promotes epithelial‐mesenchymal transition (EMT) and its expression correlates with HCC growth, invasiveness, and metastasis. During the early stages of HCC, transforming growth factor β1 (TGF‐β1) acts as a tumor suppressor; however in advanced stages, HCC cells lose their cytostatic response to TGF‐β1 and undergo EMT. Here, we investigated the role of Gal1 on liver endothelial cell biology, and the interplay between Gal1 and TGF‐β1 in HCC progression. By Western blot and immunofluorescence, we analyzed Gal1 expression, secretion and localization in HepG2 and HuH‐7 human HCC cells, and in SK‐HEP‐1 human liver sinusoidal endothelial cells (SECs). We used loss‐of‐function and gain‐of‐function experiments to down‐ or up‐regulate Gal1 expression, respectively, in HepG2 cells. We cultured SK‐HEP‐1 cells with conditioned media from HCC cells secreting different levels of Gal1, and demonstrated that Gal1 derived from tumor hepatocytes induced its own expression in SECs. Colorimetric and scratch‐wound assays revealed that secretion of Gal1 by HCC cells induced SEC proliferation and migration. Moreover, by fluorescence microscopy we demonstrated that Gal1 promoted glycan‐dependent heterotypic adhesion of HepG2 cells to SK‐HEP‐1 SECs. Furthermore, TGF‐β1 induced Gal1 expression and secretion by HCC cells, and promoted HepG2 cell adhesion to SK‐HEP‐1 SECs through a Gal1‐dependent mechanism. Finally, Gal1 modulated HepG2 cell proliferation and sensitivity to TGF‐β1‐induced growth inhibition. Our results suggest that Gal1 and TGF‐β1 might function coordinately within the HCC microenvironment to regulate tumor growth, invasion, metastasis, and angiogenesis. J. Cell. Physiol. 231: 1522–1533, 2016. © 2015 Wiley Periodicals, Inc.