Galectin-1 controls the proliferation and migration of liver sinusoidal endothelial cells and their interaction with hepatocarcinoma cells

MANZI, MALENA; BACIGALUPO, MARIA L.; CARABIAS, PABLO; ELOLA, MARIA TERESA; WOLFENSTEIN-TODEL, CARLOTA; RABINOVICH, GABRIEL A.; ESPELT, MARIA V.; TRONCOSO, MARIA F.

JOURNAL OF CELLULAR PHYSIOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2016 vol. 231 p. 1522 - 1533

0021-9541

Galectin-1 (Gal1), aâ-galactoside-binding protein abundantly expressed in hepatocellular carcinoma(HCC), promotes epithelial-mesenchymal transition (EMT)and correlates with HCC growth, invasiveness and metastasis. During the earlystages of HCC, transforming growth factor â1 (TGF-â1)acts as a tumor suppressor; however in advanced stages, HCC cells lose theircytostatic response to TGF-â1and undergo EMT. Here, we investigated the role of Gal1 on liver endothelialcell biology, and the contribution and interplay between Gal1 and TGF-â1 in HCC progression. By Western blot andimmunofluorescence, we analyzed Gal1 expression, secretion and localization inHepG2 and HuH-7 human HCC cells, and in SK-HEP-1 human liver sinusoidalendothelial cells (SECs). We used loss-of-function and gain-of-functionexperiments to down- or up-regulate Gal1 expression, respectively, in HepG2cells. We cultured SK-HEP-1 cells with conditioned media from HCC cellssecreting different levels of Gal1, and demonstratedthat tumorigenic hepatocyte-derived Gal1 induced its ownexpression in SECs. MTS colorimetric andscratch-wound assays revealed that secretion of Gal1 by HCC cells inducedSEC proliferation and migration, respectively. Interestingly, by fluorescencemicroscopy we demonstrated that Gal1 promoted glycan-dependent heterotypicadhesion of HepG2 cells to SK-HEP-1 SECs. Furthermore, TGF-â1induced Gal1 expression and secretion by HCC cells, and promoted HepG2 cell adhesion to SK-HEP-1 SECs through a Gal1expression-dependent mechanism. Notably, Gal1 modulated HepG2 cellproliferation and sensitivity to TGF-â1-induced growth inhibition. Our results suggest that Gal1 and TGF-â1might function coordinately withinthe HCC microenvironment to regulate tumor growth, invasion, metastasis andangiogenesis.