The disturbance of lipid metabolism by the TNF-alpha /PLEKHA5/FCRLA axis leads to the proliferation, invasion and metastasis of cutaneous malignant melanoma
Background: Cutaneous malignant melanoma (CMM) is one of the most highly fatal cancers; its pathogenesis requires study. We recognize that abnormalities in lipid metabolism may be associated with the risk of CMM development; nevertheless, the role of lipid metabolism in the proliferation, invasion, and metastasis of CMM remains unclear.Methods: Lipid metabolism-related genes were identified in MsigDB. A lipid metabolism-related predictive model was constructed in TCGA-SKCM using univariate Cox regression analysis, consensus cluster analysis, WGCNA analysis, LASSO regression analysis, and outcomes-related genes were identified.Immunohistochemistry, qPCR, and western blotting were used to identify essential genes, construct stable lentivirus strains, and study the biological role of PLEKHA5 in CMM cells. Transcriptomic and proteomic sequencing, protein-protein molecular docking, CO-IP, and GST pull-down were performed on the cells with knockout essential genes to explore this genes upstream and downstream regulatory mechanisms. After analyzing the results of lipid metabolomics sequencing, the effects of the essential lipids related to CMM cells after the gene knockdown were studied.Results: A predictive model was established, Risk Score = -0.009 * UBE2L6 + 0.033 * PLEKHA5 + 0.024 * LHB + 0.036 * CARM1 + 0.016 * PRXL2B + 0.131 * PLA2G4D. PLEKHA5 was identified as an essential gene, and PLEKHA5 was positively correlated with poor outcomes in CMM patients. PLEKHA5 is more highly expressed than melanocytes in CMM, which promotes the proliferation, invasion, and metastasis of CMM. FCRLA is the downstream gene of PLEKHA5, upregulated in CMM, and the primary enrichment pathway is the TNF-alpha-NFKB signaling pathway. TNF-alpha is also an essential cytokine that promotes CMM proliferation and metastasis. Hex1Cer(d18:1/26:2) and Cer(d18:2/26:2) in the downstream were significantly decreased, while ChE(0:0), ChE(18:0) and TG(18:0/16:0/19:0) in the downstream were significantly increased. The cholesterol ester inhibitor avasimibe inhibits CMM proliferation, metastasis, and invasion.Conclusion: The predictive model of CMM related to lipid metabolism established in this study has good predictive ability. PLEKHA5 is an essential biomarker related to lipid metabolism in CMM. TNFalpha-PLEKHA5-FCRLA is a signal axis that promotes proliferation, metastasis, and invasion of CMM. Its downstream product, the cholesterol ester inhibitor avasimibe, may treat CMM.