ABSTRACT
Tight junction (TJ) proteins are involved in a number of cellular functions, including paracellular barrier formation, cell polarization, differentiation, and proliferation. Altered expression of TJ proteins was reported in various epithelial tumors. Here, we used tissue samples of human cutaneous squamous cell carcinoma (SCC), its precursor tumors, as well as sun-exposed and non-sun-exposed skin as a model system to investigate TJ protein alteration at various stages of tumorigenesis. We identified that a broader localization of zonula occludens protein (ZO)-1 and claudin-4 (Cldn-4) as well as downregulation of Cldn-1 in deeper epidermal layers is a frequent event in all the tumor entities as well as in sun-exposed skin, suggesting that these changes result from chronic UV irradiation. In contrast, SCC could be distinguished from the precursor tumors and sun-exposed skin by a frequent complete loss of occludin (Ocln). To elucidate the impact of down-regulation of Ocln, we performed Ocln siRNA experiments in human keratinocytes and uncovered that Ocln downregulation results in decreased epithelial cell-cell adhesion and reduced susceptibility to apoptosis induction by UVB or TNF-related apoptosis-inducing ligand (TRAIL), cellular characteristics for tumorigenesis. Furthermore, an influence on epidermal differentiation was observed, while there was no change of E-cadherin and vimentin, markers for epithelial-mesenchymal transition. Ocln knock-down altered Ca(2+)-homeostasis which may contribute to alterations of cell-cell adhesion and differentiation. As downregulation of Ocln is also seen in SCC derived from other tissues, as well as in other carcinomas, we suggest this as a common principle in tumor pathogenesis, which may be used as a target for therapeutic intervention.
Subject(s)
Carcinoma, Squamous Cell/genetics , Cell Transformation, Neoplastic/radiation effects , Epithelial-Mesenchymal Transition/radiation effects , Gene Expression Regulation, Neoplastic/radiation effects , Keratinocytes/radiation effects , Occludin/genetics , Skin Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Calcium/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Adhesion/radiation effects , Cell Differentiation/radiation effects , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Claudins/genetics , Claudins/metabolism , Female , Homeostasis/radiation effects , Humans , Keratinocytes/cytology , Keratinocytes/metabolism , Male , Middle Aged , Neoplasm Grading , Occludin/antagonists & inhibitors , Occludin/metabolism , RNA, Small Interfering/genetics , Signal Transduction/radiation effects , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tight Junctions/metabolism , Tight Junctions/pathology , Tight Junctions/radiation effects , Young Adult , Zonula Occludens-1 Protein/genetics , Zonula Occludens-1 Protein/metabolismABSTRACT
A variety of tight junction (TJ) proteins including claudins, occludin, tricellulin, zonula occludens-proteins and junctional adhesion molecules have been identified in complex localization patterns in mammalian epidermis. Their expression and/or localization is frequently altered in skin diseases including skin tumors. However, our understanding of the function(s) of TJ and TJ proteins in the skin is, even though rapidly increasing, still limited. This review summarizes our current knowledge of the involvement of TJ and TJ proteins in mammalian skin in functions ascribed to TJ in simple epithelia, such as barrier function, polarity, gene expression, proliferation, differentiation, and vesicle transport.
