TGF-β-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by pro-inflammatory cytokines derived from RAW 264.7 macrophage cells
TGF-β-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by pro-inflammatory cytokines derived from RAW 264.7 macrophage cells
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DOI：
10.1093/jb/mvr136
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发表时间：
2012-02-01
影响因子：
2.7
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
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作者：
Kawata, Mikiko;Koinuma, Daizo;Miyazono, Kohei
癌细胞在侵袭和转移过程中经历上皮-间质转化（EMT）。虽然转化生长因子- β (tgf - β)和促炎细胞因子与EMT有关，但其潜在的分子机制仍有待阐明。在这里，我们研究了来自小鼠巨噬细胞系RAW 264.7的促炎细胞因子对tgf - β诱导的A549肺癌细胞EMT的影响。RAW 264.7细胞与条件培养基共培养和处理增强了A549细胞中tgf - β诱导的一部分EMT表型，包括细胞形态的改变和间充质标记物表达的诱导。脂多糖对RAW 264.7细胞的处理增加了这些作用，还诱导了各种促炎细胞因子的表达，包括tnf - α和IL-1 β。tnf - α中和抗体可部分抑制条件培养基对RAW 264.7细胞的影响。脱氢甲基环氧喹诺霉素是一种选择性NF κ B抑制剂，部分抑制tgf - β、tnf - α和IL-1 β对纤维连接蛋白表达的增强，但对N-cadherin表达没有作用。其他药理抑制剂的作用也提示了tnf - α刺激诱导的tgf - β诱导的EMT表型的复杂调节机制。这些发现为RAW 264.7衍生的tnf - α对A549细胞中tgf - β诱导的EMT的影响提供了直接证据，这部分是由NF κ B信号转导的。
Cancer cells undergo epithelial-mesenchymal transition (EMT) during invasion and metastasis. Although transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines have been implicated in EMT, the underlying molecular mechanisms remain to be elucidated. Here, we studied the effects of proinflammatory cytokines derived from the mouse macrophage cell line RAW 264.7 on TGF-beta-induced EMT in A549 lung cancer cells. Co-culture and treatment with conditioned medium of RAW 264.7 cells enhanced a subset of TGF-beta-induced EMT phenotypes in A549 cells, including changes in cell morphology and induction of mesenchymal marker expression. These effects were increased by the treatment of RAW 264.7 cells with lipopolysaccharide, which also induced the expression of various proinflammatory cytokines, including TNF-alpha and IL-1 beta. The effects of conditioned medium of RAW 264.7 cells were partially inhibited by a TNF-alpha neutralizing antibody. Dehydroxy methyl epoxyquinomicin, a selective inhibitor of NF kappa B, partially inhibited the enhancement of fibronectin expression by TGF-beta, TNF-alpha, and IL-1 beta, but not of N-cadherin expression. Effects of other pharmacological inhibitors also suggested complex regulatory mechanisms of the TGF-beta-induced EMT phenotype by TNF-alpha stimulation. These findings provide direct evidence of the effects of RAW 264.7-derived TNF-alpha on TGF-beta-induced EMT in A549 cells, which is transduced in part by NF kappa B signalling.