Two opposite effects of desmoglein 3 on the growth of oral squamous cell carcinoma between anchorage -dependent and -independent conditions

Desmoglein 3 (Dsg3), a desmosomal cadherin, is aberrantly expressed in oral squamous cell carcinoma (OSCC), although its role remains controversial. Higher Dsg3 expression has been reported in metastatic lymph nodes compared with primary tumors. This study aimed to clarify the role of Dsg3 under anchorage-dependent (AD) and anchorage-independent (AID) conditions. Cell lines derived from primary tumors (P) and metastatic lymph nodes (LY) of three OSCC patients, along with two commercial OSCC cell lines, were analyzed for proliferation, migration, and multicellular aggregate (MCA) formation. Differentially expressed genes (DEGs) following Dsg3 knockdown were also examined, followed by Gene Ontology (GO) analysis. Under AD conditions, Dsg3-low cells showed significantly higher proliferation and migration than Dsg3-high cells (p < 0.05). In contrast, under AID conditions, Dsg3 expression was markedly upregulated (up to 50-fold), and Dsg3-high cells exhibited enhanced proliferation. However, Dsg3 knockdown significantly increased proliferation under AD conditions but had no significant effect under AID conditions. Instead, under AID conditions, Dsg3 knockdown significantly reduced aggregate size and increased variability in circularity, indicating impaired structural organization of MCAs. Consistent with these findings, DEG analysis revealed no enrichment of apoptosis- or cell cycle–related pathways under AID conditions. GO analysis indicated that DEGs under AD conditions were associated with macromolecule biosynthesis, whereas those under AID conditions were related to gene expression and nucleic acid biosynthesis. These results indicate that Dsg3 exerts anchorage-dependent functions in OSCC, suppressing proliferation under AD conditions while contributing to the structural organization of multicellular aggregates under AID conditions. This context-dependent role may underlie the paradoxical effects of Dsg3 and facilitate tumor adaptation to metastatic environments.