Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interieukin-6 expression
Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interieukin-6 expression
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DOI：
10.1002/ijc.23973
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发表时间：
2009-01-15
影响因子：
6.4
通讯作者：
Li, Gang
中科院分区：
文献类型：
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作者：
Karst, Alison M.;Gao, Kai;Li, Gang
核因子κ B（NF-κ B）信号转导在许多肿瘤类型中失调，导致NF-κ B转录复合物的异常表达和/或活化。我们以前曾报道NF-κ B B亚单位p50的核表达与黑色素瘤进展和患者5年生存率低密切相关。在这项研究中，我们使用cDNA微阵列分析过表达NF-κ B p50的黑色素瘤细胞的基因表达谱。我们发现，NF-κ B p50的表达强烈诱导白细胞介素-6（IL-6）在黑色素瘤细胞中的转录和翻译水平的上调，并且黑色素瘤细胞产生的IL-6在体外增强了内皮细胞的生长。转录激活因子3（ATF 3）的表达，IL-6基因转录的负调控因子，抑制p50介导的IL-6上调。使用基于慢病毒的shRNA敲低p50表达废除了黑色素瘤细胞中的IL-6诱导，并抑制其对内皮细胞生长的影响。最后，我们使用了体内基质胶塞试验，表明NF-κ B p50过表达促进血管生成，而NF-κ B p50沉默抑制血管形成。我们的研究结果首次证明NF-κ B p50亚基通过特异性上调IL-6介导黑色素瘤血管生成，突出了NF-κ B p50/IL-6信号传导轴在黑色素瘤进展中的新的重要作用。(c)2008 Wiley-Liss，Inc.
Nuclear factor kappa B (NF-kappa B) signaling is deregulated in many tumor types, resulting in aberrant expression and/or activation of NF-kappa B transcriptional complexes. We have previously reported that nuclear expression of the NF-kappa B subunit p50 is strongly correlated with melanoma progression and poor 5-year patient survival. In this study, we used cDNA microarray to analyze the gene expression profiles of melanoma cells overexpressing NF-kappa B p50. We found that NF-kappa B p50 expression strongly induced interleukin-6 (IL-6) upregulation in melanoma cells at both the transcriptional and translational levels and that IL-6 production by melanoma cells enhanced the growth of endothelial cells in vitro. Expression of activating transcription factor 3 (ATF3), a negative regulator of IL-6 gene transcription, inhibited p50-mediated IL-6 upregulation. Knockdown of p50 expression using lentiviral-based shRNA abrogated IL-6 induction in melanoma cells and inhibited its effects on endothelial cell growth. Finally, we used an in vivo matrigel plug assay to show that NF-kappa B p50 overexpression promotes angiogenesis, while silencing NF-kappa B p50 inhibits blood vessel formation. Our results demonstrate for the first time that the NF-kappa B p50 subunit mediates melanoma angiogenesis by specifically upregulating IL-6, highlighting a novel and important role for the NF-kappa B p50/IL-6 signaling axis in melanoma progression. (c) 2008 Wiley-Liss, Inc.