Involvement of HIF-1 in invasion of Mum2B uveal melanoma cells.

The propensity of uveal melanoma cells for invasion and metastasis is critical factor for the clinical outcome of this form of cancer, and the essential biology of its aggressiveness is not completely understood. In the present study we investigated the involvement of hypoxia-inducible factor 1 (HIF-1) in uveal melanoma migration, invasion and adhesion, the hallmarks of aggressive behavior of cancer cells. We demonstrate that exposure to hypoxia increased migration, invasion and adhesion of uveal melanoma cells in in vitro assays. The "silencing" of HIF-1alpha, the oxygen-regulated subunit of HIF-1, using RNA interference technology resulted in a marked decrease of the uveal melanoma cell migration, invasion and adhesion. GeneChip microarray analysis revealed that a number of genes which regulate cancer invasion and metabolism such as CXCR4, angiopoietin-related protein, pyruvate dehydrogenase kinase 1 (PDK1) are also activated by hypoxia in a HIF-1-dependent manner in Mum2B uveal melanoma cells. We further demonstrate that serum deprivation resulted in HIF-1 and CXCR4 activation, suggesting specific metabolic regulation of HIF-1 in these cells. Microarray analysis of serum-deprived cells identified among the upregulated genes a number of cancer invasion-related genes, some of them being known HIF-1-regulated targets. Taken together, these results suggest that the involvement of HIF-1 in uveal melanoma tumorigenesis is significant and complex, and that metabolic regulation of HIF-1 activation in Mum2B uveal melanoma cells has its specificities.