1830

DSG3

desmoglein 3;DSG3;desmoglein 3

130 kDa pemphigus vulgaris antigen|130-kD pemphigus vulgaris antigen|cadherin family member 6|desmoglein-3|pemphigus vulgaris antigen

18q12.1

protein-coding

OBJECTIVES: To investigate the correlation between the percentage of metastatic tumor present in lymph nodes resected from patients with squamous cell carcinoma of the head and neck (HNSCC) and level of expression of 3 marker genes: pemphigus vulgaris antigen (PVA), parathyroid hormone-related peptide (PTHrP), and tumor-associated calcium signal transducer 1 (TACSTD1). In addition, we investigated whether the level of expression of these 3 markers was associated with clinical outcomes for patients with HNSCC. STUDY DESIGN: Retrospective analysis of previously harvested patient samples. SETTING: The University of Pittsburgh. SUBJECTS AND METHODS: A total of 448 lymph nodes from 92 patients with HNSCC were evaluated for expression of the gene markers PVA, PTHrP, and TACSTD1 using real-time polymerase chain reaction. Confirmation of metastasis was determined by histologic examination. The expression level of these markers versus tumor percentage was analyzed. RESULTS: All 3 markers were studied independently and were associated with tumor percentage in metastatic lymph nodes. PVA had the strongest correlation, followed by PTHrP and then TACSTD1. PVA levels had a trend toward association with clinical outcome, specifically time to death caused by cancer, but this was confounded by tumor stage. CONCLUSION: All 3 tumor gene markers were associated with percentage of tumor cells in metastatic lymph nodes. PVA had the strongest correlation. PVA may add prognostic utility beyond pathologic staging, but this requires analysis of a larger cohort. Prospective studies of tumor volume in metastatic nodes should determine a lower limit threshold of molecular marker detection.

Desmoglein 3 (Dsg3), the pemphigus vulgaris antigen, has recently been shown to be upregulated in squamous cell carcinoma (SCC) and has been identified as a good tumor-specific marker for clinical staging of cervical sentinel lymph nodes in head and neck SCC. However, little is known about its biological function in cancer. The actin-binding protein Ezrin and the activator protein 1 (AP-1) transcription factor are implicated in cancer progression and metastasis. Here, we report that Dsg3 regulates the activity of c-Jun/AP-1 as well as protein kinase C (PKC)-mediated phosphorylation of Ezrin-Thr567, which contributes to the accelerated motility of cancer cells. Ectopic expression of Dsg3 in cancer cell lines caused enhanced phosphorylation at Ezrin-Thr567 with concomitant augmented membrane protrusions, cell spreading and invasive phenotype. We showed that Dsg3 formed a complex with Ezrin at the plasma membrane that was required for its proper function of interacting with F-actin and CD44 as Dsg3 knockdown impaired these associations. The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantially by various pharmacological inhibitors for Ser/Thr kinases, including PKC and Rho kinase that are known to activate Ezrin. Furthermore, a marked increase in c-Jun S63 phosphorylation, among others, was found in Dsg3-overexpressing cells and the activation of c-Jun/AP-1 was further supported by a luciferase reporter assay. Taken together, our study identifies a novel Dsg3-mediated c-Jun/AP-1 regulatory mechanism and PKC-dependent Ezrin phosphorylation that could be responsible for Dsg3-associated cancer metastasis.

Desmocollin 3 (Dsc3) and desmoglein 3 (Dsg3) are both transmembrane glycoproteins that belong to the cadherin family of calcium-dependent cell adhesion molecules. beta-Catenin is a member of the cadherin-catenin complex that mediates homotypic cell-cell adhesion and is also an important molecule in the wnt signaling pathway. In this study, we examined the simultaneous expression level of Dsc3, Dsg3, and beta-catenin in oral squamous cell carcinomas (OSCCs) and normal oral epithelia using immunohistochemistry. There was a significant correlation (p < 0.05) among the following variables in OSCCs: reduced or loss of expression of Dsc3, Dsg3, and beta-catenin compared to normal oral epithelium, reduced or loss of expression of Dsc3 and histological grade (moderately or poorly differentiated), and reduced or loss of expression of beta-catenin and lymph node metastasis. Furthermore, a positive correlation was found between reduced or loss of beta-catenin staining and reduced or loss of Dsc3 staining in lymph node metastatic cancer tissue (r = 0.734, p < 0.05). These results suggest an abnormal expression of Dsc3, Dsg3, and beta-catenin induced in the progression of oral carcinomas and that the Dsc3 expression level might be related to the regulation of beta-catenin in lymph node metastasis and cell proliferation in OSCCs.