RESUMEN
Tight junctions (TJs) are cellcell adhesion structures frequently altered by oncogenic transformation. In the present study the role of human papillomavirus (HPV) 16 E7 oncoprotein on the sealing of TJs was investigated and also the expression level of claudins in mouse cervix and in epithelial MadinDarby Canine Kidney (MDCK) cells. It was found that there was reduced expression of claudins 1 and 10 in the cervix of 7monthold transgenic K14E7 mice treated with 17ßestradiol (E2), with invasive cancer. In addition, there was also a transient increase in claudin1 expression in the cervix of 2monthold K14E7 mice, and claudin10 accumulated at the border of cells in the upper layer of the cervix in FvB mice treated with E2, and in K14E7 mice treated with or without E2. These changes were accompanied by an augmented paracellular permeability of the cervix in 2 and 7monthold FvB mice treated with E2, which became more pronounced in K14E7 mice treated with or without E2. In MDCK cells the stable expression of E7 increased the space between adjacent cells and altered the architecture of the monolayers, induced the development of an acute peak of transepithelial electrical resistance accompanied by a reduced expression of claudins 1, 2 and 10, and an increase in claudin4. Moreover, E7 enhances the ability of MDCK cells to migrate through a 3D matrix and induces cell stiffening and stress fiber formation. These observations revealed that cell transformation induced by HPV16 E7 oncoprotein was accompanied by changes in the pattern of expression of claudins and the degree of sealing of epithelial TJs.
Asunto(s)
Claudinas/biosíntesis , Papillomavirus Humano 16/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecciones por Papillomavirus/metabolismo , Uniones Estrechas/metabolismo , Neoplasias del Cuello Uterino/virología , Animales , Células Cultivadas , Claudinas/genética , Claudinas/metabolismo , Modelos Animales de Enfermedad , Perros , Femenino , Papillomavirus Humano 16/aislamiento & purificación , Humanos , Ratones , Ratones Transgénicos , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
Ions and molecules move across epithelial barriers by two pathways, the transcellular and the paracellular. The former is taken by lipophilic compounds, or by ions and molecules that move across the plasma membrane through pumps, carriers or exchangers. The second route is regulated by the tight junction (TJ) that through paracellular channels, allows the transport of ions across epithelial barriers. Since, a wide variety of bioactive molecules like peptides, proteins and oligonucleotides cannot use the transcellular route, due to their hydrophilic nature, interest has arisen in devising procedures to open the TJ in a reversible manner for paracellular drug delivery. Here, we describe how different strategies have been devised to enhance the paracellular intestinal absorption of drugs; to open the blood-brain barrier (BBB) to allow the penetration of drugs for the treatment of disorders and tumors of the central nervous system; or to deliver antigens into the subjacent mucosa associated lymphoid tissues, for the development of mucosal vaccines. The strategies described, include the use of peptides, antibodies and miRNAs that target proteins of the apical junctional complex, as well as toxins derived from microorganisms that open the TJ by inducing the contraction of the cortical actomyosin ring. Also, we describe how paracellular absorption, is enhanced by drugs that extract cholesterol from the plasma membrane, surfactants, fatty acids, oligosaccharides, cationic polymers, nitric oxide donors and calcium chelators. Likewise, we explain how the BBB has been opened by employing tumor necrosis factor-α, bradykinin, short chain alkylglycerols, hyperosmotic mannitol and focused ultrasound.