Desmoglein 2 Depletion Leads to Increased Migration and Upregulation of the Chemoattractant Secretoneurin in Melanoma Cells

Abstract

During development and progression of malignant melanoma, an important role has been attributed to alterations of cell-cell adhesions, in particular, to a “cadherin switch” from E- to N-cadherin. We have previously shown that a subtype of melanoma cells express the desmosomal cadherin desmoglein 2 as non-junction-bound cell surface protein in addition to classical cadherins. To study the role of desmoglein 2 in melanoma cells, melanoma lines containing high endogenous amounts of desmoglein 2 were depleted of the protein by RNA interference. Transwell migration and scratch wounding assays showed markedly increased migration upon desmoglein 2 suppression whereas proliferation and viability remained unaltered. In gene expression profiles, desmoglein 2 depletion was associated with overexpression of migration-related genes. Strongest overexpression was found for secretogranin II which has not been reported in melanoma cells before. The bioactive peptide derived from secretogranin II, secretoneurin, is known to exert chemoattractive functions and was demonstrated here to stimulate melanoma cell migration. In summary, we show that desmoglein 2 expression attenuates migration of melanoma cells. The mechanism of desmoglein 2 impaired cell migration is mediated by downregulation of secretogranin II. Loss of desmoglein 2 increases expression of secretogranin II, followed by an enhanced migratory activity of melanoma cells. Our data add a new pathway of regulating melanoma cell migration related to a desmoglein 2 – secretogranin II axis.

Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome

“…However, DSG2 is increasingly recognized to also play important biological functions unrelated to desmosome formation [20, 21, 24, 36–38]. Most notably for the present study, recent data implicate DSG2 in regulating the angiogenic activity of ECs, whereby loss of function disrupts tube formation on Matrigel and in vivo neoangiogenesis, and is associated with defective angiogenesis in patients with systemic sclerosis [24] (Ebert et al , submitted).…”

“…We therefore repeated these experiments with C32 cells but found no effect of either siRNA. Thus, using two different assays, we could not reproduce the reported [21] increase in melanoma cell migration upon DSG2 knockdown. Note that, for each of these functional assays using DSG2 knockdown, efficiency of knockdown was confirmed by flow cytometric analysis of DSG2 expression on the day of the assay (not shown).…”

“…Previous studies have shown that DSG2 can regulate several biological processes in addition to its canonical function in desmosomal adhesion, including proliferation and cell death in epithelial cells [36–38], actin cytoskeletal architecture in ECs [24] and melanoma cell migration [21]. We thus assessed the effect of DSG2 inhibition on these parameters in melanoma cells, to determine whether they could contribute to the observed reduction in tube formation.…”

“…Surprisingly, while melanoma cells are not thought to generate desmosomes, expression of DSG2 in this cell type has been described [20–22], though another study failed to detect DSG2 expression in human melanoma biopsies [23]. The biological function of DSG2 in melanoma remains poorly defined, although one study has linked its expression to the regulation of melanoma cell motility [21]. …”

Cadherin flexibility provides a key difference between desmosomes and adherens junctions

“…Dsg2 is the most ubiquitous desmosomal cadherin, expressed in all desmosome-forming tissues including epithelia, myocardium, and lymph nodes (11). Dsg2 is highly expressed in melanoma cells (12), and mutations in Dsg2 are lethal in familial arrhythmogenic right ventricular dysplasia (13). Sequence similarity suggests that desmosomal cadherins have a domain structure similar to that of type 1 cadherins (6).…”