Aldose Reductase Inhibition Prevents Colon Cancer Growth by Restoring Phosphatase and Tensin Homolog Through Modulation of miR-21 and FOXO3a
Aldose Reductase Inhibition Prevents Colon Cancer Growth by Restoring Phosphatase and Tensin Homolog Through Modulation of miR-21 and FOXO3a
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DOI：
10.1089/ars.2012.4643
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发表时间：
2013-04-01
影响因子：
6.6
通讯作者：
Srivastava, Satish K.
中科院分区：
文献类型：
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作者：
Saxena, Ashish;Tammali, Ravinder;Srivastava, Satish K.
目的：我们之前已经证明，醛糖还原酶（AR）是一种氧化应激反应蛋白，抑制醛糖还原酶（AR）可以在体外和体内阻止结肠癌细胞的生长。微核糖核酸（miR）表达的改变可以通过调节参与肿瘤生长和转移的关键基因的功能表达来促进癌症的发生。然而，AR在癌细胞中调控miR表达及其依赖性有丝分裂作用的分子机制尚不清楚。因此，我们研究了AR如何调节生长因子诱导的miRs表达和结肠癌细胞的生长。结果：抑制AR可显著下调生长因子诱导的人结肠癌细胞、HT29、SW480和Caco-2中miR-21的表达。此外，AR抑制还增加了结肠癌细胞中的磷酸酶和紧张素同源物（PTEN） （miR-21的直接靶点）和叉头盒O3A （FOXO3a）。我们用FOXO3a siRNA消融HT29细胞获得的结果显示，激活蛋白1 （AP-1）激活和miR-21表达增加，表明FOXO3a通过AP-1失活来抑制miR-21。AR的抑制也阻止了表皮生长因子诱导的磷脂酰肌醇3-激酶（PI3K）、丝氨酸/苏氨酸激酶（AKT）、c-Jun、c-Fos、PTEN和FOXO3a的磷酸化，以及AP-1的脱氧核糖核酸（DNA）结合活性。更重要的是，在人类大肠癌异种移植组织中，AR抑制剂处理小鼠的miR-21表达较低，PTEN和FOXO3a水平显著高于对照组。创新：这些发现证明了AR在调节miR-21及其靶点PTEN在生长因子诱导的结肠癌细胞生长中的新作用。结论：总的来说，这些结果表明AR通过活性氧(ROS)/PI3K/AKT/AP-1调节miR-21、PTEN和FOXO3a的表达，在调节生长因子诱导的结肠癌生长中发挥了新的作用。Antioxid。氧化还原信号，18,1249-1262。
Aims: We have shown earlier that inhibition of aldose reductase (AR), an oxidative stress-response protein, prevents colon cancer cell growth in vitro and in vivo. Changes in microribonucleic acid (miR) expression can contribute to cancer by modulating the functional expression of critical genes involved in cancer growth and metastasis. However, the molecular mechanisms by which AR regulates miR expression and their dependent mitogenic effects in cancer cells are not known. Therefore, we investigated how AR regulates growth factor-induced expression of miRs and growth of colon cancer cells. Results: Inhibition of AR significantly downregulated growth factor-induced miR-21 expression in human colon cancer cells, HT29, SW480, and Caco-2. Further, AR inhibition also increased phosphatase and tensin homolog (PTEN) (a direct target of miR-21) and forkhead box O3A (FOXO3a) in colon cancer cells. Our results obtained with HT29 cells ablated with FOXO3a siRNA showed increased activator protein-1 (AP-1) activation and miR-21 expression, indicating that FOXO3a represses miR-21 via AP-1 inactivation. Inhibition of AR also prevented the epidermal growth factor-induced phosphorylation of phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), c-Jun, c-Fos, PTEN, and FOXO3a, and deoxyribonucleic acid (DNA)-binding activity of AP-1. More importantly, in human colon adenocarcinoma xenograft tissues, miR-21 expression was lower, and PTEN and FOXO3a levels were significantly higher in AR inhibitor-treated mice compared to controls. Innovation: These findings demonstrate a novel role of AR in the regulation of miR-21 and its target PTEN in growth factor-induced colon cancer cell growth. Conclusions: Collectively, these results show a novel role of AR in mediation of growth factor-induced colon cancer growth by modulating miR-21, PTEN, and FOXO3a expression through reactive oxygen species (ROS)/PI3K/AKT/AP-1. Antioxid. Redox Signal. 18, 1249-1262.