Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression

Abstract

Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1 þ/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1 þ/lacZ mice) or the superficial epidermis (Inv-Dsg2/Ptc1 þ/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1 e/e BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, in both an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.

Upregulation of desmoglein 2 and its clinical value in lung adenocarcinoma: a comprehensive analysis by multiple bioinformatics methods

“…DSG2 knockdown also downregulated cyclin-dependent kinase 2 expression and upregulated p27 expression in NSCLC (Cai et al, 2017). A recent study showed that overexpression of DSG2 induced STAT3 phosphorylation and further increased Gli1 levels in basal cell carcinomas (Brennan-Crispi et al, 2019). DSG2 can be a prognostic marker in cancers.…”

DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer

“…Overmiller et al [21] suggested that in skin squamous cell carcinoma, DSG2 stimulated cell growth and migration by positively regulating EGFR levels and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms. Brennan-Crispi et al [22] showed that in skin basal cell carcinoma and squamous cell carcinoma, DSG2 enhanced canonical hedgehog signaling downstream of Ptc1 to promote cancer development through the activation of phosphorylated Stat3 and regulation of Gli1 expression. Katharina et al [23] identified a novel promigratory pathway of pancreatic cancer cells in which the loss of DSG2 reduces the levels of plakoglobin via deregulated MAPK signaling.…”

DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer

“…Overmiller et al [21] suggested that in skin squamous cell carcinoma, DSG2 stimulated cell growth and migration by positively regulating EGFR levels and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms. Brennan-Crispi et al [22] showed Our study was the rst to investigate the relationship between DSG2 expression and lymphangiogenesis. Coexpression analyses showed that DSG2 was positively correlated with CCBE1, which positively regulated lymphangiogenesis, while it was negatively correlated with VASH1, which negatively regulated lymphangiogenesis.…”