Figure 6.

Subcellular and molecular events in oral carcinogenesis. This scheme provides a summary of subcellular and molecular changes observed during oral carcinogenesis. These changes include the Wnt3a expression, nuclear detection of β-catenin, endosome enlargement and the activation status of Rab5 GTPase. We propose a model whereby oral carcinogenesis is associated with the progressive expression of Wnt3a and the consequent stabilization and nuclear translocation of β-catenin. These events are accompanied by the continuous activation of Rab5-GTPase, endosome enlargement and the increased sequestration of the destruction complex within endosomes (see main text for details). Color codes represent the Wnt3a expression (green bar), nuclear β-catenin detection (blue bar), Rab5 activity (red bar) and early endosome size (yellow bar). The lighter the color, the lower the expression/detection/activity/size. The darker the color, the higher the expression/detection/activity/size for each case. The Wnt3a representation summarizes evidence obtained from immunohistochemical analyses in clinical samples and in vitro measurements of ligand secretions in cell culture models. The nuclear β-catenin representation summarizes evidence obtained in both clinical samples and cell culture models. The nuclear detection progressively increases from normal oral mucosa through the different stages of oral dysplasia (mild, moderate and severe); however, the nuclear detection of this protein decreases in OSCC. The Rab5 activity (Rab5-GTP levels) has been measured in cell culture models and is shown substantially increased in dysplastic oral keratinocytes (models of moderate/severe dysplasia) in comparison with nondysplastic oral keratinocytes and OSCC cells. The endosomal size (early endosomes) has been measured by tissue immunofluorescence in clinical samples of normal mucosa and mild, moderate and severe dysplasia, as well as in cell culture models, using different markers of early endosomes (the interrogation symbol indicates that this has not been explored in OSCC).