HPV16-E6 Oncoprotein Activates TGF-βand Wnt/β-Catenin Pathways in the Epithelium-Mesenchymal Transition of Cataracts in a Transgenic Mouse Model

Abstract

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.

Mir-195-5p targets Smad7 regulation of the Wnt/β-catenin pathway to promote osteogenic differentiation of vascular smooth muscle cells

“…Osteogenic differentiation has also been established to be regulated by the Wnt/β-catenin pathway [ 15 , 16 ], with which Smad7 is closely associated [ 17 ]. Bao et al have reported that Smad7 mediates the SOX7 and Axin-2 regulation of the Wnt/β-catenin pathway to influence to progression of breast cancer [ 18 ], whereas by targeting Smad7, miR-15b inhibit the osteogenic differentiation of bone mesenchymal stem cells [ 19 ].…”

Synthesis of N‐aminophalimides derived from α‐amino acids: Theoretical study to find them as HDAC8 inhibitors by docking simulations and in vitro assays

“…On this background, our research has been interesting in the synthesis of compounds derived from α‐amino acids and in researching their biological properties, for instance, we have synthesized and carried out docking studies and in vitro assays of some 2,3‐dihydro‐1 H ‐isoindole derived from α‐amino acids as channel blockers, Cox‐1 and ‐2 inhibitors, effect over HDAC8 activity and expression, and HDACs inhibitors, as well as effect on the K14E6 transgenic mouse model (Mancilla et al, 2001; Mancilla‐Percino et al, 2010, 2016; Rodríguez‐Uribe et al, 2018, 2020; Santamaria‐Herrera et al, 2016; Trejo Muñoz et al, 2014).…”

“…On this background, our research has been interesting in the synthesis of compounds derived from αamino acids and in researching their biological properties, for instance, we have synthesized and carried out docking studies and in vitro assays of some 2,3-dihydro-1H-isoindole derived from αamino acids as channel blockers, Cox-1 and -2 inhibitors, effect over HDAC8 activity and expression, and HDACs inhibitors, as well as effect on the K14E6 transgenic mouse model (Mancilla et al, 2001;Mancilla-Percino et al, 2010Rodríguez-Uribe et al, 2018, 2020Santamaria-Herrera et al, 2016;Trejo Muñoz et al, 2014). Thus, continuing with our studies, in this work, we present the synthesis of novel N-aminophalimides 5(ac) and 6(a-c) derived from αamino acids, which have the phthalimide moiety as analogous compounds studied as anticancer agents and HDAC inhibitors, as well as new 3(a-c), 4(a-c) acetamides as precursors of Naminophalimides.…”