Interferon alpha 2a downregulates VEGF expression through PI3 kinase and MAP kinase signaling pathways

An earlier report demonstrated that interferon alpha (IFN-alpha) inhibited tumor growth and recurrence in an MHCC97 xenograft model in nude mice by suppressing tumor angiogenesis rather than by inhibiting tumor cell proliferation. However, the underlying molecular mechanism was not fully elucidated. In this study, we demonstrated that IFN-alpha 2a could downregulate VEGF expression both in mRNA and in protein levels, as well as downregulating HIF-1alpha mRNA expression in MHCC97 cells in vitro. A cDNA micro array analysis followed by Northern and Western blot analysis revealed that PI3 kinase and MAP kinase signaling pathways might be inhibited by IFN-alpha 2a. Blocking the function of IFN-alpha receptor with a specific peptide could eliminate the inhibitory effects of IFN-alpha 2a on VEGF expression. In addition, wortmannin and PD098059, respective inhibitors of the PI3 kinase and the MAP kinase signaling pathways, when used independently or in combination, could also downregulate the VEGF synthesis and secretion in a similar pattern of IFN-alpha 2a. These observations may lead to the conclusion that IFN-alpha 2a could suppress VEGF synthesis and secretion by downregulating HIF-1alpha expression, via inhibition of the PI3 kinase and/or the MAP kinase signaling pathways.