Abstract
During the evolution of epithelial cancers, cells often lose their characteristic features and acquire a mesenchymal phenotype, in a process known as epithelial-mesenchymal transition (EMT). In the present study we followed early stages of keratinocyte transformation by HPV16, and observed diverse cellular changes, associated with EMT. We compared primary keratinocytes with early and late passages of HF1 cells, a cell line of HPV16-transformed keratinocytes. We have previously shown that during the progression from the normal cells to early HF1 cells, immortalization is acquired, while in the progression to late HF1, cells become anchorage independent. We show here that during the transition from the normal state to late HF1 cells, there is a progressive reduction in cytokeratin expression, desmosome formation, adherens junctions and focal adhesions, ultimately leading to poorly adhesive phenotype, which is associated with anchorage-independence. Surprisingly, unlike “conventional EMT”, these changes are associated with reduced Rac1-dependent cell migration. We monitored reduced Rac1-dependent migration also in the cervical cancer cell line SiHa. Therefore we can conclude that up to the stage of tumor formation migratory activity is eliminated.
Highlights
Epithelial-mesenchymal transition (EMT) is a developmental process characterized by the loss of cell-cell adhesion, leading to cell individualization, which is accompanied by increased cell motility
In this study we used HPV16-transformed keratinocytes in an attempt to explore the cellular changes that occur at early stages of transformation
In the primary keratinocytes we observed massive distribution of cytokeratin bundles throughout the cell, while early HF1 cells had a delicate network of intermediate filaments, which was further reduced upon progression to late HF1 cells (Figure 1A)
Summary
Epithelial-mesenchymal transition (EMT) is a developmental process characterized by the loss of cell-cell adhesion, leading to cell individualization, which is accompanied by increased cell motility. The most prominent phenotypic change associated with keratinocyte transformation is the reduction in cell-cell adhesion. Normal keratinocytes form a multi-layered sheet, held together by robust cell-cell adhesions, dominated by dense arrays of actin-associated adherens junctions and cytokeratin-bound desmosomes. During EMT, these intercellular junctions are down-regulated, leading to the loss of epithelial coherence [1,2,3,4]. Adherens junctions connect epithelial cells through homotypic interactions mediated by E-Cadherin molecules. A reduction in desmosome formation during EMT correlates with conspicuous alterations in intermediate filaments; cytokeratins, almost disappear from within the cell, while the mesenchymaltype intermediate filament protein, vimentin, is up-regulated [2,6,7,8]. EMT is commonly associated with increased cell migration, which enables cells to dissociate from their original tissue and form metastasis in distant organs. Increased migratory capacity often depends on Rac activity, which induces lamellipodia formation and focal complex assembly [9]
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