Interleukin-32 alpha induces migration of human melanoma cells through downregulation of E-cadherin

Abstract

Interleukin (IL)-32 alpha, the shortest isoform of proinflammatory cytokine IL32, is associated with various inflammatory diseases and cancers. However, its involvement in human melanoma is not understood. To determine the effect of IL-32 alpha in melanoma, IL-32 alpha levels were examined in human melanoma cell lines that exhibit different migratory abilities. IL-32 alpha levels were higher in human melanoma cell lines with more migratory ability. An IL-32 alpha-overexpressing G361 human melanoma cell line was generated to investigate the effect of IL-32 alpha on melanoma migration. IL-32 alpha-overexpressing G361 cells (G361-IL-32 alpha) exhibit an increased migratory ability compared to vector control cells (G361-vector). To identify factors involved in IL-32 alpha-induced migration, we compared expression of E-cadherin in G361-vector and G361-IL-32 alpha cells. We observed decreased levels of E-cadherin in G361-IL-32 alpha cells, resulting in F-actin polymerization. To further investigate signaling pathways related to IL-32 alpha-induced migration, we treated G361-vector and G361-IL-32 alpha cells with PD98059, a selective MEK inhibitor. Inhibition of Erk1/2 by PD98059 restored E-cadherin expression and decreased IL-32 alpha-induced migration. In addition, cell invasiveness of G361-IL-32 alpha cells was tested using an in vivo lung metastasis model. As results, lung metastasis was significantly increased by IL-32 alpha overexpression. Taken together, these data indicate that IL-32 alpha induced human melanoma migration via Erk1/2 activation, which repressed E-cadherin expression. Our findings suggest that IL-32 alpha is a novel regulator of migration in melanoma.