TGF-β1 downregulates COX-2 expression leading to decrease of PGE2 production in human lung cancer A549 cells, which is involved in fibrotic response to TGF-β1.
TGF-β1 downregulates COX-2 expression leading to decrease of PGE2 production in human lung cancer A549 cells, which is involved in fibrotic response to TGF-β1.
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DOI：
10.1371/journal.pone.0076346
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kojima S
中科院分区：
文献类型：
--
作者：
Takai E;Tsukimoto M;Kojima S
转化生长因子-β 1（TGF-β1）是一种多功能细胞因子，参与多种病理生理过程，包括癌症进展和纤维化疾病。在这里，我们发现，TGF-β1（5 ng/mL）处理诱导下调环氧合酶-2（考克斯-2），导致前列腺素E2（PGE 2）的合成减少，在人肺癌A549细胞。用考克斯-2或PGE 2受体的特异性抑制剂处理细胞导致生长抑制，表明考克斯-2/PGE 2途径以自分泌方式促进增殖。TGF-β1处理诱导生长抑制，而外源性PGE 2可减弱这种抑制。TGF-β1也是上皮间质转化（EMT）的有效诱导剂，EMT是上皮细胞分化为成纤维细胞的表型变化。与EP 1/3激动剂硫前列酮相比，补充PGE 2或PGE 2受体EP 4激动剂PGE 1-乙醇可抑制TGF-β1诱导的纤维连接蛋白和I型胶原（细胞外基质成分）的表达。外源性PGE 2或PGE 2受体激动剂也能抑制TGF-β1诱导的肌动蛋白重构。这些结果表明PGE 2具有抗纤维化作用。结论：TGF-β1下调考克斯-2/PGE 2信号通路参与了A549细胞的纤维化EMT反应。
Transforming growth factor-ß1 (TGF-β1) is a multifunctional cytokine that is involved in various pathophysiological processes, including cancer progression and fibrotic disorders. Here, we show that treatment with TGF-β1 (5 ng/mL) induced downregulation of cyclooxygenase-2 (COX-2), leading to reduced synthesis of prostaglandin E2 (PGE2), in human lung cancer A549 cells. Treatment of cells with specific inhibitors of COX-2 or PGE2 receptor resulted in growth inhibition, indicating that the COX-2/PGE2 pathway contributes to proliferation in an autocrine manner. TGF-β1 treatment induced growth inhibition, which was attenuated by exogenous PGE2. TGF-β1 is also a potent inducer of epithelial mesenchymal transition (EMT), a phenotype change in which epithelial cells differentiate into fibroblastoid cells. Supplementation with PGE2 or PGE2 receptor EP4 agonist PGE1-alcohol, as compared with EP1/3 agonist sulprostone, inhibited TGF-β1-induced expression of fibronectin and collagen I (extracellular matrix components). Exogenous PGE2 or PGE2 receptor agonists also suppressed actin remodeling induced by TGF-β1. These results suggest that PGE2 has an anti-fibrotic effect. We conclude that TGF-β1-induced downregulation of COX-2/PGE2 signaling is involved in facilitation of fibrotic EMT response in A549 cells.
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