Increased ROS production in non-polarized mammary epithelial cells induces monocyte infiltration in 3D culture
Increased ROS production in non-polarized mammary epithelial cells induces monocyte infiltration in 3D culture
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DOI：
10.1242/jcs.186031
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Xu, Ren
中科院分区：
文献类型：
--
作者：
Li, Linzhang;Chen, Jie;Xu, Ren
上皮细胞极性的丧失促进细胞侵袭和癌症扩散。因此，识别破坏极化腺泡形成的因素至关重要。活性氧 (ROS) 会促进癌症进展并促进炎症。在这里，我们发现，在三维 (3D) 培养中，非极化乳腺癌细胞系 T4-2 产生的 ROS 水平显着高于极化 S1 和 T4R 细胞，并伴有核因子 kappa B (NF-kappa B) 通路和细胞因子表达的诱导。使用抗氧化剂最大限度地减少 T4-2 细胞中的 ROS，重建基础极性并抑制细胞增殖。引入组成型激活的 RAC1 会破坏细胞极性并增加 ROS 水平，表明 RAC1 是连接细胞极性和 ROS 生成的关键调节因子。我们还使用 3D 共培养系统将单核细胞浸润与极化腺泡结构的破坏联系起来。功能获得和丧失实验表明，非极化细胞中 ROS 的增加对于增强单核细胞募集是必要且充分的。 ROS 还诱导细胞因子表达和 NF-κ B 活性。这些结果表明，乳腺上皮细胞中ROS产生的增加导致细胞极性破坏并促进单核细胞浸润。
Loss of epithelial cell polarity promotes cell invasion and cancer dissemination. Therefore, identification of factors that disrupt polarized acinar formation is crucial. Reactive oxygen species (ROS) drive cancer progression and promote inflammation. Here, we show that the non-polarized breast cancer cell line T4-2 generates significantly higher ROS levels than polarized S1 and T4R cells in three-dimensional (3D) culture, accompanied by induction of the nuclear factor kappa B (NF-kappa B) pathway and cytokine expression. Minimizing ROS in T4-2 cells with antioxidants reestablished basal polarity and inhibited cell proliferation. Introducing constitutively activated RAC1 disrupted cell polarity and increased ROS levels, indicating that RAC1 is a crucial regulator that links cell polarity and ROS generation. We also linked monocyte infiltration with disruption of polarized acinar structure using a 3D co-culture system. Gain-and loss-of-function experiments demonstrated that increased ROS in non-polarized cells is necessary and sufficient to enhance monocyte recruitment. ROS also induced cytokine expression and NF-kappa B activity. These results suggest that increased ROS production in mammary epithelial cell leads to disruption of cell polarity and promotes monocyte infiltration.