Mutual enhancement between heparanase and vascular endothelial growth factor: A novel mechanism for melanoma progression

Heparanase is closely related to growth factors in the role of promoting tumor progression. Among them, vascular endothelial growth factor (VEGF) is necessary for tumor vascularity and metastasis. Release of VEGF by heparanase can initiate relative signaling pathways, resulting in an up-regulation of transcriptional factors related with heparanase. Therefore, VEGF likely has a potential function as a regulator of heparanase expression in melanoma. We hypothesized that a novel mechanism exists where heparanase and VEGF are mutually enhanced in melanoma. Our study was conducted to validate the hypothetical mutual enhancement and elucidate its effect on melanoma progression. We found that the addition of exogenous VEGF and its cDNA transfection induce heparanase over-expression by means of western-blot and real-time RT-PCR, while anti-VEGF siRNA reduces heparanase expression in A2058 and WM793 melanoma cell lines. Likewise, VEGF expression is also regulated by heparanase in these two cell lines. Additionally, the cells with mutual enhancement phenotypes exhibit higher proliferation and transmigration capacity. PD98059, a specific inhibitor of the MEK/ERK signaling pathway, is involved in this mutual enhancement. These data are the first to show that heparanase and VEGF have a mutual enhancement in melanoma cells, which may be a novel mechanism for promoting melanoma progression.