Methylseleninic acid activates Keap1/Nrf2 pathway via up-regulating miR-200a in human oesophageal squamous cell carcinoma cells.
Methylseleninic acid activates Keap1/Nrf2 pathway via up-regulating miR-200a in human oesophageal squamous cell carcinoma cells.
复制标题
甲基硒酸通过上调人食管鳞状细胞癌细胞中的miR-200a激活Keap1/Nrf2通路
DOI：
10.1042/bsr20150092
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发表时间：
2015-09-04
影响因子：
4
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Liu M;Hu C;Xu Q;Chen L;Ma K;Xu N;Zhu H
甲基亚硒酸（Methylseleninic acid，MSA）作为第二代硒化合物，可激活食管鳞癌细胞KLF 4/miR-200 a/Keap 1/Nrf 2通路。食管鳞状细胞癌（ESCC）在中国某些地区的发病率非常高。越来越多的证据表明硒具有潜在的抗食管癌作用，但其确切机制尚不完全清楚。甲基亚硒酸（MSA）作为第二代硒化合物，是一种很有前途的化学预防剂。以往的研究表明，kelch样ECH相关蛋白1（Keap 1）/核因子E2相关因子2（Nrf 2）系统在癌症预防中起着关键作用，但对ESCC细胞中MSA的相关性知之甚少。在本研究中，我们观察到MSA处理显著下调ESCC细胞中Keap 1，诱导Nrf 2的核积累，并增强抗氧化反应元件（ARE）启动子活性。MSA还能显著诱导miR-200 a的表达，并直接抑制Keap 1的表达。Antagomir-200 a可减弱MSA处理诱导的ESCC细胞中Keap 1的下调。此外，MSA诱导的miR-200 a表达依赖于Krüpple样因子4（KLF 4）的介导。这些结果证实了MSA通过调节KLF 4/miR-200 a/Keap 1/Nrf 2轴在ESCC细胞中作为化学预防剂的潜在作用。
Methylseleninic acid (MSA), as a potent second-generation selenium compound, could activate KLF4/miR-200a/Keap1/Nrf2 pathway in oesophageal squamous cell carcinoma cells. Oesophageal squamous cell carcinoma (ESCC) occurs at a very high rates in certain regions of China. There are increasing evidences demonstrating that selenium could act as a potential anti-oesophageal cancer agent, but the precise mechanisms involved are still not completely understood. Methylseleninic acid (MSA), as a potent second-generation selenium compound, is a promising chemopreventive agent. Previous studies demonstrated that the kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) system plays a critical role in cancer prevention, but little is known about its association with MSA in ESCC cells. In the present study, we observed that MSA treatment significantly down-regulated Keap1, induced nuclear accumulation of Nrf2 and enhance the antioxidant response element (ARE) promoter activity in ESCC cells. MSA could also significantly induce miR-200a expression and inhibit Keap1 directly. Antagomir-200a could attenuate MSA treatment-induced Keap1 down-regulation in ESCC cells. Moreover, MSA-induced miR-200a expression was dependent on the mediation of Krüpple-like factor 4 (KLF4). These results reaffirm the potential role of MSA as a chemopreventive agent via the regulation of KLF4/miR-200a/Keap1/Nrf2 axis in ESCC cells.