Desmogleins (DSGs) are a family of cadherins of four known subfamily members, DSG1-4. DSG3 functions as a cell-cell adhesion receptor in desmosome junctions, responsible for mediating cell adhesion and desmosome formation. It was initially described in Pemphigus Vulgaris, an autoimmune skin blistering disorder caused by binding of auto-antibodies against the extracellular domain of DSG3. Studies have reported impaired cell-cell adhesive function following DSG3 depletion from desmosomes.

In normal tissues, DSG3 staining is membrane localized on epithelial cells in skin, kidney, and esophagus. Recently, DSG3 was described as a positive biomarker of squamous cell carcinoma (SqCC), discriminating lymph node metastasis in head and neck SqCC between positive and benign nodes with ~100% accuracy. Additionally, DSG3 staining had a sensitivity of 99% and specificity of 87% for SqCC in primary tumors from multiple organ sites. DSG3 was also shown as a marker in differentiating lung SqCC from other non-small cell lung cancer subtypes, staining positively in 98% of SqCC and negatively in 99% of non-SqCC cases. Positive DSG3 staining was also significantly correlated with a favorable prognosis, while down-regulation is associated with a loss of differentiation and enhanced metastasis.