SEL1L exerts a pro-tumorigenic/pro-angiogenic function in human skin melanoma

Suppressor/enhancer of Lin-12-like (SEL1L) is a component of the endoplasmic reticulum-associated degradation (ERAD) pathway which is part of the unfolded protein response (UPR). SEL1L may exert pro-tumorigenic or oncosuppressive functions in different tumor types, but its role in human cutaneous malignant melanoma (cMM) remains largely unexplored. Here, in silico analysis revealed that SEL1L is upregulated in cMM compared to normal skin. In addition, SEL1L expression in cMM positively correlated with Clark level at diagnosis, higher expression being associated with poorer patient survival. SEL1L co-expression with ERAD- and UPR-related genes, along with Gene Ontology enrichment analysis, supported its role in ER-stress responses in cMM. Immunohistochemistry and quantitative digital morphometric analysis of SEL1L protein levels in 60 human samples of benign melanocytic tumors and cMMs at different Breslow T category showed that SEL1L levels in cMM progressively increase in association with T category, tumor thickness, and the presence of ulceration. In addition, total and tumor-associated endothelial SEL1L expression correlates with microvessel density in the corresponding tumor specimens. In keeping with a non-redundant role of SEL1L in cMM, grafting of SEL1L-silenced A2058 human melanoma cells in immunodeficient mice yielded tumors with reduced cell proliferation, enhanced apoptosis, and increased necrosis, accompanied by heightened hypoxia and reduced vascularization. Accordingly, SEL1L-silenced cells showed upregulation of the angiosuppressive thrombospondin-encoding genes THSP1 and THSP2 and a reduced angiogenic potential in an endothelial sprouting assay in vitro and in the chick embryo chorionallantoic membrane assay in vivo. Together, these findings indicate that SEL1L may exert a pro-tumorigenic/pro-angiogenic function in human melanoma and pave the way to further studies aimed at investigating its potential as a therapeutic target in cMM.