Galectin-8 induces partial epithelial-mesenchymal transition with invasive tumorigenic capabilities involving a FAK/EGFR/proteasome pathway in Madin-Darby canine kidney cells

• Published in: Molecular biology of the cell 2018-03, Vol.29 (5), p.557-574
• Main Authors: Oyanadel, Claudia, Holmes, Christopher, Pardo, Evelyn, Retamal, Claudio, Shaughnessy, Ronan, Smith, Patricio, Cortés, Priscilla, Bravo-Zehnder, Marcela, Metz, Claudia, Feuerhake, Teo, Romero, 5th, Diego, Roa, Juan Carlos, Montecinos, Viviana, Soza, Andrea, González, Alfonso
• Format: Article
• Language: English
• Subjects: Animals; Cadherins - metabolism; Carcinogenesis; Dogs; Epithelial-Mesenchymal Transition; ErbB Receptors - metabolism; Focal Adhesion Kinase 1 - metabolism; Galectins - metabolism; Humans; Integrin beta1 - metabolism; Madin Darby Canine Kidney Cells; Male; Mice; Neoplasms, Experimental; Proteasome Endopeptidase Complex - metabolism; Recombinant Proteins - metabolism; Signal Transduction; Transfection; Up-Regulation; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E16-05-0301

Epithelial cells can acquire invasive and tumorigenic capabilities through epithelial-mesenchymal-transition (EMT). The glycan-binding protein galectin-8 (Gal-8) activates selective β1-integrins involved in EMT and is overexpressed by certain carcinomas. Here we show that Gal-8 overexpression or exogenous addition promotes proliferation, migration, and invasion in nontumoral Madin-Darby canine kidney (MDCK) cells, involving focal-adhesion kinase (FAK)-mediated transactivation of the epidermal growth factor receptor (EGFR), likely triggered by α5β1integrin binding. Under subconfluent conditions, Gal-8-overexpressing MDCK cells (MDCK-Gal-8 ) display hallmarks of EMT, including decreased E-cadherin and up-regulated expression of vimentin, fibronectin, and Snail, as well as increased β-catenin activity. Changes related to migration/invasion included higher expression of α5β1 integrin, extracellular matrix-degrading MMP13 and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) protease systems. Gal-8-stimulated FAK/EGFR pathway leads to proteasome overactivity characteristic of cancer cells. Yet MDCK-Gal-8 cells still develop apical/basolateral polarity reverting EMT markers and proteasome activity under confluence. This is due to the opposite segregation of Gal-8 secretion (apical) and β1-integrins distribution (basolateral). Strikingly, MDCK-Gal-8 cells acquired tumorigenic potential, as reflected in anchorage-independent growth in soft agar and tumor generation in immunodeficient NSG mice. Therefore, Gal-8 can promote oncogenic-like transformation of epithelial cells through partial and reversible EMT, accompanied by higher proliferation, migration/invasion, and tumorigenic properties.