Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive
tumor cells to mimic the pattern of embryonic vasculogenic networks.
Hypoxia plays a pivotal role in the formation of VM.
Hypoxia-induced Bcl-2 overexpression is observed in many types of
tumors including
melanoma, in which it is associated with tumorigenicity and angiogenesis.
VE-cadherin, the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation, is also overexpressed in
melanoma. Despite these connections, whether
hypoxia induces VM formation via
VE-cadherin regulation by Bcl-2 is not confirmed. We used human
melanoma cells to upregulate or knockdown the expression of Bcl-2 to investigate the possible molecular mechanism of VM formation under
hypoxia. Bcl-2 overexpression increased
VE-cadherin expression and VM formation under normoxia, whereas Bcl-2
siRNA significantly decreased
VE-cadherin expression and VM formation under
hypoxia. We then demonstrated that Bcl-2 regulated
VE-cadherin transcription activity by Western blot, three-dimensional cultures, reporter gene assay, and clinical analysis. Therefore, Bcl-2-dependent
VE-cadherin overexpression may be an important mechanism by which
hypoxia induces VM.