Interferon alpha 2a downregulates VEGF expression through PI3 kinase and MAP kinase signaling pathways
Interferon alpha 2a downregulates VEGF expression through PI3 kinase and MAP kinase signaling pathways
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干扰素 α 2a 通过 PI3 激酶和 MAP 激酶信号通路下调 VEGF 表达
DOI：
10.1007/s00432-004-0615-2
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发表时间：
2005-03-01
影响因子：
3.6
通讯作者：
Liu, KD
中科院分区：
文献类型：
--
作者：
Wu, WZ;Sun, HC;Liu, KD
早期的报道表明，干扰素α（IFN-α）通过抑制肿瘤血管生成而不是抑制肿瘤细胞增殖来抑制裸鼠MHCC 97异种移植模型中的肿瘤生长和复发。然而，潜在的分子机制尚未完全阐明。在本研究中，我们证明了IFN-α 2a可以在mRNA和蛋白水平上下调VEGF的表达，以及在体外下调MHCC 97细胞中HIF-1 α mRNA的表达。cDNA微阵列分析以及北方和Western印迹分析显示，IFN-α 2a可能抑制PI 3激酶和MAP激酶信号通路。用特异性肽段阻断IFN-α受体功能可消除IFN-α 2a对VEGF表达的抑制作用。此外，当单独或组合使用时，渥曼青霉素和PD 098059（各自的PI 3激酶和MAP激酶信号传导途径的抑制剂）也可以以与IFN-α 2a类似的模式下调VEGF的合成和分泌。这些观察结果可能导致的结论是，IFN-α 2a可以通过下调HIF-1 α的表达，通过抑制PI 3激酶和/或MAP激酶信号通路抑制VEGF的合成和分泌。
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.