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Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-to-mesenchymal transition and migration of breast epithelial cells

机译：NOx4参与TGF-β和SMAD3驱动的诱导上皮 - 间充质转换和乳房上皮细胞的迁移

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The epithelial-to-mesenchymal transition (EMT) is the development of increased cell plasticity that occurs normally during wound healing and embryonic development and can be coopted for cancer invasion and metastasis. TGF-beta induces EMT but the mechanism is unclear. Our studies suggest Nox4, a member of the NADPH oxidase (Nox) family, is a source of reactive oxygen species (ROS) affecting cell migration and fibronectin expression, an EMT marker, in normal and metastatic breast epithelial cells. We found TGF-beta induces Nox4 expression (mRNA and protein) and ROS generation in normal (MCF10A) and metastatic (MDA-MB-231) human breast epithelial cells. Conversely, cells expressing a dominant-negative form of Nox4 or Nox4-targeted shRNA showed significantly lower ROS production upon TGF-beta treatment. Expression of a constitutively active TGF-beta receptor type I significantly increased Nox4 promoter activity, mRNA and protein expression, and ROS generation. Nox4 transcriptional regulation by TGF-beta was SMAD3-dependent based on the effect of constitutively active SMAD3 increasing Nox4 promoter activity, whereas dominant-negative SMAD3 or SIS3, a SMAD3-specific inhibitor, had the opposite effect. Furthermore, Nox4 knockdown, dominant-negative Nox4 or SMAD3, or SIS3 blunted TGF-beta induced wound healing and cell migration, whereas cell proliferation was not effected. Our experiments further indicate Nox4 plays a role in TGF-beta regulation of fibronectin mRNA expression, based on the effects of dominant-negative Nox4 in reducing fibronectin mRNA in TGF-beta treated MDA-MB-231and MCF10A cells. Collectively, these data indicate Nox4 contributes to NADPH oxidase-dependent ROS production that may be critical for progression of the EMT in breast epithelial cells, and thereby has therapeutic implications.
机译：上皮 - 间充质转换（EMT）是在伤口愈合和胚胎发育期间通常发生的细胞塑性的发展，可以用于癌症侵袭和转移。 TGF-Beta诱导EMT，但机制尚不清楚。我们的研究表明NOX4，NADPH氧化酶（NOx）家族的成员，是影响细胞迁移和纤连蛋白表达，EMT标记，正常和转移性乳腺上皮细胞的反应性氧物质（ROS）的源。我们发现TGF-β诱导NOx4表达（mRNA和蛋白）和ROS在正常（MCF10A）和转移性（MDA-MB-231）人乳腺上皮细胞中产生的ROS产生。相反，表达TGF-β处理的ROS产生显着降低了表达显性阴性形式的NOx4或NOX4靶标鼠的细胞。组成型活性TGF-β受体类型I显着增加了NOX4启动子活性，mRNA和蛋白表达和ROS生成。 TGF-β的NOx4转录调节基于组成型活性SMAD3增加的NOX4启动子活性的效果，而显性阴性SMAD3或SIS3，SMAD3特异性抑制剂具有相反的效果。此外，NOx4敲低，显性阴性NOx4或SMAD3，或SIS3钝化TGF-β诱导的伤口愈合和细胞迁移，而不能进行细胞增殖。我们的实验进一步表示NOx4在TGF-βmRNA表达中发挥作用，基于显性阴性NOx4在TGF-β处理的MDA-MB-231和MCF10A细胞中减少纤连蛋白mRNA中的纤维连接蛋白mRNA的影响。总的来说，这些数据表明NOX4有助于NADPH氧化酶依赖性ROS产生，这对于乳腺上皮细胞中EMT的进展至关重要，从而具有治疗性意义。

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