HPV16-E6 Oncoprotein Activates TGF-β and Wnt/β-Catenin Pathways in the Epithelium-Mesenchymal Transition of Cataracts in a Transgenic Mouse Model
2018
Genaro Rodríguez-Uribe | Nicolas Serafín-Higuera | Gabriela Damian-Morales | Enoc Mariano Cortés-Malagón | Vicky García-Hernández | Odette Verdejo-Torres | Jessica Paulina Campos-Blázquez | Cynthia R. Trejo-Muñoz | Rubén Gerardo Contreras | Rodolfo Ocadiz-Delgado | Carmen Palacios-Reyes | Paul F. Lambert | Anne E. Griep | Teresa Mancilla-Percino | Jaime Escobar-Herrera | Elizabeth Álvarez-Ríos | Carlos Ugarte-Briones | José Moreno | Patricio Gariglio | José Bonilla-Delgado
Objective. This work aimed to determine if cataractous changes associated with EMT occurring in the K14E6 mice lenses are associated with TGF-β and Wnt/β-catenin signaling activation. Materials and Methods. Cataracts of K14E6 mice were analysed histologically; and components of TGF-β and Wnt/β-catenin signaling were evaluated by Western blot, RT-qPCR, in situ RT-PCR, IHC, or IF technics. Metalloproteinases involved in EMT were also assayed using zymography. The endogenous stabilisation of Smad7 protein was also assessed using an HDAC inhibitor. Results. The K14E6 mice, which displayed binocular cataracts in 100% of the animals, exhibited loss of tissue organisation, cortical liquefaction, and an increase in the number of hyperproliferative-nucleated cells with mesenchymal-like characteristics in the lenses. Changes in lenses’ cell morphology were due to actin filaments reorganisation, activation of TGF-β and Wnt/β-catenin pathways, and the accumulation of MTA1 protein. Finally, the stabilisation of Smad7 protein diminishes cell proliferation, as well as MTA1 protein levels. Conclusion. The HPV16-E6 oncoprotein induces EMT in transgenic mice cataracts. The molecular mechanism may involve TGF-β and Wnt/β-catenin pathways, suggesting that the K14E6 transgenic mouse could be a useful model for the study or treatment of EMT-induced cataracts.
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