Abstract
The contribution of adherens junction inactivation, typically by downregulation or mutation of the transmembrane core component E-cadherin, to cancer progression is well recognized. In contrast, the role of the desmosomal cadherin components of the related cell-cell adhesion junction, the desmosome, in cancer development has not been well explored. Here, we use mouse models to probe the functional role of desmosomal cadherins in carcinogenesis. Because mice lacking the desmosomal cadherin Desmoglein 3 (Dsg3) have revealed a crucial role for Dsg3 in cell-cell adhesion in stratified epithelia, we investigate the consequence of Dsg3 loss in two models of skin carcinogenesis. First, using Dsg3−/− keratinocytes, we show that these cells display adhesion defects in vitro and compromised tumor growth in allograft assays, suggesting that Dsg3 enables tumor formation in certain settings. In contrast, using an autochthonous model for SCC development in response to chronic UVB treatment, we discover a surprising lack of enhanced tumorigenesis in Dsg3−/− mice relative to controls, unlike mice lacking the desmosomal component Perp. Accordingly, there is no defect in the apoptotic response to UVB or enhanced immune cell infiltration upon Dsg3 loss that could promote tumorigenesis. Thus, Dsg3 does not display a clear function as a tumor suppressor in these mouse skin cancer models. Continued unraveling of the roles of Dsg3 and other desmosomal constituents in carcinogenesis in different contexts will be important for ultimately improving cancer diagnosis, prognostication, and treatment.
Highlights
The vast majority of human cancers, known as carcinomas, arise from epithelia
Desmoglein 3 (Dsg3) Loss Compromises Adhesion in Keratinocytes To characterize the role of Dsg3 in cultured primary keratinocytes, we first analyzed the impact of Dsg3 loss on desmosome function using mouse keratinocytes grown in high calcium medium to induce desmosome formation
No differences were found in the solubilization properties of desmosome proteins in Dsg32/2 and wild-type keratinocytes, increased levels of the other desmogleins, Perp, and Pkp3 were detected in the insoluble fraction of Dsg32/2 keratinocytes compared to controls (Fig. 1B)
Summary
The vast majority of human cancers, known as carcinomas, arise from epithelia. Defining the factors that govern the normal architecture and function of epithelia, and how these can be perturbed, is essential for understanding cancer development. Whereas adherens junctions are fundamental both for intercellular adhesion in epithelia and for enabling the dynamic rearrangements of epithelia [2], desmosomes are pivotal for reinforcing adhesion between epithelial cells via anchorage to the intermediate filament network [1,3]. The cytoplasmic domains of these transmembrane cadherins interact with members of the armadillo protein family known as plakophilins (PKP1-3) and plakoglobin (PG), which connect to the intermediate filament network through desmoplakins (DSP1 and 2). Another important desmosome component, revealed through genetic knockout and immunogold electron microscopy studies, is the tetraspan membrane protein Perp. Perp null mice display profound blistering of the oral mucosa and skin due to fewer and structurally abnormal desmosomes [10]
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