Multicentre Prospective Study on Mucosal Associated Invariant T Cells in Patients with Melanoma

Background: Vault particles are highly conserved ribonucleoprotein cargo delivery nanodevices present exclusively in eukaryotes.They are formed through the self-oligomerization of 78 monomers of Major Vault Protein (MVP, 100 kDa), enclosing vault RNAs (vtRNAs) along with the proteins TEP1 and VPARP in mammals.Vault particles have been implicated in various cellular functions, and their components have emerged as critical modulators of oncogenic signaling.Specifically, increased expression of MVP, the primary component of vault particles, has been associated with aggressive tumor phenotypes.MVP is also involved in regulating signaling pathways that affect tumor survival, proliferation, metastasis, and has been extensively studied in the context of multidrug resistance (MDR).However, there is currently no evidence linking MVP to the onset or resistance mechanisms in melanoma.Methods: Herein we investigated MVP's role in melanoma progress and resistant mechanisms using primary (A375), potentially metastatic (WM88), and metastatic (SKMEL5) melanoma cell lines, sensitive and resistant to Vemurafenib, a BRAF V600E inhibitor.We generated stable MVP-overexpressing melanoma cell lines and assessed their sensitivity to Vemurafenib through IC50 value determination.Biochemical assays were conducted to analyze cell proliferation and viability.RT-qPCR and Western Blot analyses evaluated the expression of key regulators involved in cancer aggressiveness, such as factors associated with the epithelial-tomesenchymal transition (EMT), cancer-related long non-coding RNAs, and cell cycle modulators (Cyclins).Results: Significant alterations in MVP expression were observed in Vemurafenib-resistant melanoma cells and overexpression of MVP led to a slight increase in sensitivity to Vemurafenib.Biochemical assays revealed alterations in the proliferation and viability of the cells, correlating with melanoma progression stages.Molecular analyses showed changes in the expression of EMT-associated factors, long non-coding RNAs, and Cyclins, indicating MVP's involvement in key regulatory pathways.Conclusions: This study provides the first evidence that MVP plays a crucial role in melanoma progression and resistance to Vemurafenib.MVP's involvement in drug resistance and key signaling pathways suggests it as a potential therapeutic target in melanoma treatment.