Galectin-1 triggers epithelial-mesenchymal transition in human hepatocellular carcinoma cells

MARÍA L BACIGALUPO, MALENA MANZI , MARÍA V ESPELT , DANIEL COMPAGNO, DIEGO LADERACH, CARLOTA WOLFENSTEIN-TODEL, GABRIEL A RABINOVICH, AND MARÍA F TRONCOSO

JOURNAL OF CELLULAR PHYSIOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2015 vol. 230 p. 1289 - 1309

0021-9541

Galectin-1 (Gal1), a β-galactoside-binding protein abundantly expressed in tumor microenvironments, is associated with the development of metastasis in hepatocellular carcinomas (HCC). However, the precise roles of Gal1 in HCC cell invasiveness and dissemination are uncertain. Here, we investigated whether Gal1 could mediate epithelial-mesenchymal transition (EMT) in HCC cells, a key process during cancer progression. We used the well-differentiated and low invasive HepG2 and HuH-7 cells and we performed ?gain-of-function? and ?loss-function? experiments by stably transfecting cells with Gal1 cDNA constructs or by knocking down Gal1 expression using siRNA strategies, respectively. Epithelial and mesenchymal markers expression, changes in apico-basal polarity and activation of specific signaling pathways were studied using Western blot and fluorescence microscopy. Moreover, cell adhesion, proliferation and soft-agar assays were performed. Gal1 up-regulation in HepG2 cells induced the down-regulation of the adherens junction protein E-cadherin and increased levels of the transcription factor Snail, one of the main inducers of EMT in HCC. Enhanced Gal1 expression facilitated the transition from epithelial cell morphology toward a fibroblastoid phenotype and favored up-regulation of the mesenchymal marker vimentin in HCC cells. Cells overexpressing Gal1 showed enhanced cell-matrix adhesion, proliferation, anchorage-independent growth and loss of apico-basal polarity. Remarkably, Gal1 promoted Akt activation, Akt-dependent β-catenin nuclear translocation and elevated levels of cyclin D1, suggesting the activation of the Wnt pathway. Furthermore, Gal1 overexpression induced E-cadherin downregulation through a PI3K/Akt-dependent mechanism. Our results provide the first evidence of a role of Gal1 as an inducer of EMT in HCC cells, with critical implications in HCC metastasis.