Melanoma, a relatively common malignancy, has become one of the tumors with the fastest rising incidence in recent years.,The purpose of this study was to investigate the effect of Microglial Annexin A3 (ANXA3) on melanoma.,Serum samples were obtained from 20 patients with melanoma or 20 healthy controls.,Kaplan‐Meier survival analysis was performed.,Transcriptome were used to analyze the correlation between ANXA3 expression and overall survival in patients with melanoma.,Human melanoma cell lines WM‐115 cells were transfected with ANXA3, si‐ANXA3, ANXA3 + si‐hypoxia inducible factor‐1α (HIF‐1α), si‐ANXA3 + HIF‐1α, and negative plasmids.,Cell proliferation assay, cell invasion assay, and wound healing assay were performed on WM‐115 cells.,Lactate dehydrogenase (LDH) and caspase‐3/9 activities were detected by commercial kits.,Western blot and RT‐PCR were used to detect the protein and mRNA expression of relation factors.,ANXA3 expression was up‐regulated in patients with melanoma in comparison with healthy controls.,Over‐expression of ANXA3 promoted cell growth and migration, and reduced cytotoxicity of WM‐115 cells.,Overall survival (OS) and disease‐free survival (DFS) of patients with high ANXA3 expression were both lower than those of patients with low ANXA3 expression.,Down‐regulation of ANXA3 reduced cell growth and migration, and promoted cytotoxicity of WM‐115 cells.,ANXA3 induced vascular endothelial growth factor (VEGF) signaling pathway by activation of HIF‐1α.,In conclusion, our results indicated that ANXA3 promoted cell growth and migration of melanoma via activation of HIF‐1α/VEGF signaling pathway.,ANAX3 promoted cell growth and migration of melanoma via activation of Hif‐1α/VEGF signalling pathway.
Detachment of cells from the primary tumour precedes metastatic progression by facilitating cell release into the tissue.,Solid tumours exhibit altered pH homeostasis with extracellular acidification.,In human melanoma, the Na+/H+ exchanger NHE1 is an important modifier of the tumour nanoenvironment.,Here we tested the modulation of cell-cell-adhesion by extracellular pH and NHE1.,MV3 tumour spheroids embedded in a collagen matrix unravelled the efficacy of cell-cell contact loosening and 3D emigration into an environment mimicking physiological confinement.,Adhesive interaction strength between individual MV3 cells was quantified using atomic force microscopy and validated by multicellular aggregation assays.,Extracellular acidification from pHe7.4 to 6.4 decreases cell migration and invasion but increases single cell detachment from the spheroids.,Acidification and NHE1 overexpression both reduce cell-cell adhesion strength, indicated by reduced maximum pulling forces and adhesion energies.,Multicellular aggregation and spheroid formation are strongly impaired under acidification or NHE1 overexpression.,We show a clear dependence of melanoma cell-cell adhesion on pHe and NHE1 as a modulator.,These effects are opposite to cell-matrix interactions that are strengthened by protons extruded via NHE1.,We conclude that these opposite effects of NHE1 act synergistically during the metastatic cascade.