Abstract
Aberrant activation of Hedgehog (Hh) signaling is causative of BCCs and has been associated with a fraction of SCCs. Desmoglein 2 (Dsg2) is an adhesion protein that is upregulated in many cancers and overexpression of Dsg2 in the epidermis renders mice more susceptible to squamous-derived neoplasia. Here we examined a potential crosstalk between Dsg2 and Hh signaling in skin tumorigenesis. Our findings show that Dsg2 modulates Gli1 expression, in vitro and in vivo. Ectopic expression of Dsg2 on Ptc1(+/lacZ) background enhanced epidermal proliferation and interfollicular activation of the Hh pathway. Furthermore, in response to DMBA/TPA, the Dsg2/Ptc1+/lacZ mice developed squamous lessons earlier than the WT, Ptc1(+/lacZ), and Inv-Dsg2 littermates. Additionally, DMBA/TPA induced BCC formation in all mice harboring the Ptc1(+/lacZ) gene and the presence of Dsg2 in Dsg2/Ptc1(+/lacZ) mice doubled the BCC tumor burden. Reporter analysis revealed activation of the Hh pathway in the BCC tumors. However, in the SCCs we observed Hh activity only in the underlying dermis of the tumors. Furthermore, Dsg2/Ptc1(+/lacZ) mice demonstrated enhanced MEK/Erk1/2 activation within the tumors and expression of Shh in the dermis. In summary, our results demonstrate that Dsg2 modulates Hh signaling, and this synergy may accelerate skin tumor development by different mechanisms.
Highlights
Desmosomes are multi-protein, cell-cell adhesion complexes critical for tissue integrity and function [1, 2]
Expression of Shh at the transcript level was highly upregulated in the skin of Inv-Desmoglein 2 (Dsg2) mice (800fold vs. wild type (WT)), suggesting that it may account for increased Gli target gene expression in vivo (Figure 1B)
In the present study we demonstrate the existence of a generalized crosstalk between Dsg2 and Hh signaling in different cell types that promotes epidermal proliferation, accelerates squamous-derived tumorigenesis, and enhances basal cell carcinomas (BCC) development in vivo
Summary
Desmosomes are multi-protein, cell-cell adhesion complexes critical for tissue integrity and function [1, 2]. Desmoglein 2 (Dsg2), the most ubiquitously expressed desmosomal cadherin, is found in all simple epithelia and select non-epithelial cells such as cardiomyocytes [3,4,5]. Dsg is highly expressed in the hair follicles but is found only at a low level in the basal layer of the interfollicular epidermis [6]. The role of Dsg in tumorigenesis emerged with the findings that Dsg expression is highly upregulated in several epithelialderived malignancies including basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) [6]. The role of desmogleins in cell-cell adhesion has been well established [9]. We established that Dsg interacts with caveolin-1, a key regulator of cell signaling [8]. Knockdown of Dsg in colon cancer cells inhibits proliferation by suppressing EGFR signaling [9]
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