Cell gangliosides and plasma membrane sialidase NEU3 are key regulators of melanoma malignancy

Malignant melanoma is a highly aggressive tumour with increasing incidence and poor prognosis in the metastatic stage. In addition to many alterations concerning signalling pathways and oncogenes, melanoma express typical glycosphingolipids, mainly gangliosides, not displayed by melanocytes.1 We demonstrated that melanomas can be grouped into three clusters based on their ganglioside profile: cluster 1 characterized by high content of GM3, mainly in the form of N-glycolyl GM3, and GD3, cluster 2 characterized by the appearance of complex gangliosides such as GD1a and GT1b and by a low content of N-glycolyl GM3, cluster 3 characterized by low N-glycolyl GM3 and by the presence of GD1a. Significantly, these three clusters were associated with different malignant properties such as growth in soft agar and apoptosis resistance, and with different patients\u2019 survival (from a median survival of 10 months to complete healing). Melanoma ganglioside pattern was determined by distinct alterations concerning enzymes involved in ganglioside metabolism. In particular, we detected the up-regulation of plasma membrane sialidase NEU3. We demonstrated that, above all in melanomas classified into cluster 1, the high activity of NEU3 contributed to reduce the levels of N-acetyl GM3 in favour of N-glycolyl GM3. This event appeared to strongly alter cell surface dynamics and signalling. In fact, NEU3 silencing promoted the increase of N-acetyl GM3 and, in parallel, reverted the epithelial-mesenchymal transition typical of invasive melanoma cells: the expression of E-cadherin and caveolin 1 increased, the expression of N-cadherin and several integrin, including \u3b21, \u3b23, \u3b24 and \u3b15, decreased. These molecular changes were associated with a marked decrease of the potential of migration and growth in soft agar. Based on these results, sialidase NEU3 could be considered a novel potential target in melanoma therapy. 1. Furukawa K et al (2008) Proteomics. 8(1