Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells.
Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells.
复制标题
对低氧响应的MMP-1表达的调节取决于转移性膀胱癌细胞的细胞内氧化还原状态。
DOI：
10.1016/j.bbadis.2015.09.001
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Hempel N
中科院分区：
文献类型：
--
作者：
Shin DH;Dier U;Melendez JA;Hempel N
高稳态活性氧（ROS）的产生与转移性疾病的进展有关。我们提供了新的证据表明，这种增加的细胞内ROS环境独特地倾向于转移性肿瘤细胞缺氧介导的调节基质金属蛋白酶MMP-1。使用细胞培养转移进展模型，我们先前报道了与其非转移性253 J亲本细胞相比，高转移性253 J-BV膀胱癌细胞中稳态细胞内H2 O2水平升高。253 J-BV细胞显示更高的基础MMP-1表达，其在缺氧条件下（1%O2）进一步增强。在非转移性253 J细胞中未观察到这种缺氧介导的MMP-1增加。低氧诱导的MMP-1增加伴随着低氧诱导转录因子（HIF）-1α和HIF-2α的稳定，以及转移性253 J-BV细胞中细胞内ROS的增加。RNA干扰研究表明，低氧介导的MMP-1表达主要依赖于HIF-2α的存在。此外，缺氧仅促进转移性253 J-BV细胞而非亲本253 J细胞的迁移和球状体生长。所观察到的HIF稳定，MMP-1的表达和缺氧下的迁移是依赖于细胞内ROS的增加，因为这些影响是衰减与抗氧化剂N-乙酰-L-半胱氨酸治疗。这些数据表明，ROS在缺氧介导的MMP-1表达中起重要作用，并且如在转移中观察到的，升高的细胞内氧化还原环境使肿瘤细胞倾向于增强的缺氧反应。它进一步支持了转移性肿瘤细胞独特地能够利用ROS的细胞内增加来驱动促转移信号传导事件的概念，并突出了恶性肿瘤中ROS和缺氧之间的重要相互作用。
High steady-state reactive oxygen species (ROS) production has been implicated with metastatic disease progression. We provide new evidence that this increased intracellular ROS milieu uniquely predisposes metastatic tumor cells to hypoxia-mediated regulation of the matrix metalloproteinase MMP-1. Using a cell culture metastatic progression model we previous reported that steady-state intracellular H2O2 levels are elevated in highly metastatic 253J-BV bladder cancer cells compared to their non-metastatic 253J parental cells. 253J-BV cells display higher basal MMP-1 expression, which is further enhanced under hypoxic conditions (1% O2). This hypoxia-mediated MMP-1 increase was not observed in the non-metastatic 253J cells. Hypoxia-induced MMP-1 increases are accompanied by stabilization of hypoxia-inducible transcription factors (HIF)-1α and HIF-2α, and a rise in intracellular ROS in metastatic 253J-BV cells. RNA interference studies show that hypoxia-mediated MMP-1 expression is primarily dependent on the presence of HIF-2α. Further, hypoxia promotes migration and spheroid outgrowth of only the metastatic 253J-BV cells and not the parental 253J cells. The observed HIF stabilization, MMP-1 expression and migration under hypoxia are dependent on increases in intracellular ROS, as these effects are attenuated by treatment with the antioxidant N-acetyl-L-cysteine. These data show that ROS play an important role in hypoxia-mediated MMP-1 expression and that an elevated intracellular redox environment, as observed in metastasis, predisposes tumor cells to an enhanced hypoxic response. It further supports the notion that metastatic tumor cells are uniquely able to utilize intracellular increases in ROS to drive pro-metastatic signaling events and highlights the important interplay between ROS and hypoxia in malignancy.