Biological Effect And Mechanism Of NAV2 In Skin Cutaneous Melanoma

Objects: Skin cutaneous melanoma is the most malignant cutaneous tumors with the highest mortality in the world.And invasion and metastasis are the main factors for the high mortality of melanoma.The molecular mechanism of invasion and metastasis is a hotspot in research of melanoma.Previous studies have identified neuron navigator 2(NAV2)as an oncogene in several human tumors.However,the role of NAV2 in the pathogenesis of cutaneous melanoma have not been clearly illustrated.Methods: we analyzed NAV2 expression in melanoma tissues and its role in prognosis by bioinformatic analysis based on TCGA and GEO databases and immunohistochemistry assay.shNAV2 and NAV2-cDNA were transfected into melanoma cell lines.To investigate the effect of NAV2 on the proliferation and invasion of melanoma,then we carried out a series of experiments including GO analysis,Pathway analysis,scratch test,Transwell assay,CCK-8 assay,EdU assay and animal models.The potential underlying mechanisms were investigated using EMT model in vitro,rescue experiment,protein-protein interaction analysis,qRT-PCR,and western blot.Results: In this study,we firstly demonstrated that NAV2 expression was increased in melanoma tissues in comparison to normal tissues.Furthermore,elevated expression of NAV2 was associated with shorter overall survival times of melanoma patients.Using the GO analysis and Pathway analysis of the genes correlated with NAV2,we revealed that NAV2 participated in multiple important biological processes such as cell migration,cell adhesion and cell proliferation.Cell and animal experiments demonstrated that NAV2 knockdown inhibited melanoma cell growth,invasion,migration and EMT.These findings suggest that the melanoma-promoting effect of NAV2 may attributed to enhanced EMT.Further bioinformatics analysis revealed that NAV2 was moderately related to SNAI2,a known EMT regulator.SNAI2 itself was shown to be an indicator of poor prognosis in SKCM patients.After knockdown of SNAI2 could suppress melanoma cells proliferation,invasion and migration in vitro.Indeed,SNAI2 silencing resulted in decreased expression of mesenchymal markers(N-cadherin and vimentin)and increased expression of the epithelial marker E-cadherin.Subsequently,the protein-protein interaction network showed that CTNNB1(also called ?-catenin)was one of the hub genes whose connective degree ranked first.?-catenin was also observed to have a high combined score with SNAI2.Then we discovered that NAV2 might facilitate melanoma cell EMT by upregulating SNAI2 through activation of the GSK-3?/?-catenin signaling pathway.Conclusions: In conclusion,our systematic experiments reveal that NAV2 might to be a positive regulator of SNAI2 by acting through the GSK-3?/?-catenin signal pathway,which induced EMT of melanoma cells,and subsequently promotes melanoma growth,migration and invasion.Our findings on the pathological mechanisms of NAV2-associated cutaneous melanoma may contribute to the development of potential therapeutic strategy for melanoma.