Oncogenic Activity of miR-650 in Prostate Cancer Is Mediated by Suppression of CSR1 Expression.
Oncogenic Activity of miR-650 in Prostate Cancer Is Mediated by Suppression of CSR1 Expression.
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DOI：
10.1016/j.ajpath.2015.03.015
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Zehua Zuo;Y. Yu;Ying Ding;Silvia Liu;A. Martin;G. Tseng;Jian-Hua Luo
中科院分区：
文献类型：
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作者：
Zehua Zuo;Y. Yu;Ying Ding;Silvia Liu;A. Martin;G. Tseng;Jian-Hua Luo
细胞应激反应 1 (CSR1) 是一种肿瘤抑制基因，其表达在前列腺癌中经常下调。然而，其下调机制尚不清楚。在这里，我们发现 CSR1 的 3' 非翻译区包含 miR-650 的靶位点。在前列腺癌样本和细胞系中发现高水平的 miR-650。特定抑制剂对 miR-650 的降解显着增加了 CSR1 的表达水平。通过荧光素酶报告系统验证了 miR-650 与其 3' 非翻译区靶位点之间的相互作用。靶位点的突变完全消除了 miR-650 在 CSR1 3'非翻译区的活性。抑制 miR-650 可逆转 CSR1 的表达抑制，抑制集落形成，并阻止 PC3 和 DU145 细胞的细胞周期进入 S 期。动物模型显示，用 miR-650 抑制剂转化的 PC3 或 DU145 细胞异种移植的严重联合免疫缺陷小鼠的肿瘤体积、转移率和死亡率显着降低。我们的分析表明，抑制 CSR1 表达是一种对于 miR-650 致癌活性至关重要的新机制。
Cellular stress response 1 (CSR1) is a tumor suppressor gene whose expression was frequently down-regulated in prostate cancer. The mechanism of its down-regulation, however, is not clear. Here, we show that the 3′ untranslated region of CSR1 contains a target site of miR-650. High level of miR-650 was found in prostate cancer samples and cell lines. Degradation of miR-650 by specific inhibitor dramatically increased the expression levels of CSR1. Interaction between miR-650 and its target site in the 3′ untranslated region was validated through luciferase reporter system. Mutation at the target site completely abrogated the activity of miR-650 on the 3′ untranslated region of CSR1. Inhibition of miR-650 reversed the expression suppression of CSR1, suppressed colony formation, and blocked cell cycle entry to the S phase of both PC3 and DU145 cells. Animal model showed significant decrease of tumor volume, rate of metastasis, and mortality of severe combined immunodeficient mice xenografted with PC3 or DU145 cells transformed with inhibitor of miR-650. Our analyses demonstrate that suppression of CSR1 expression is a novel mechanism critical for the oncogenic activity of miR-650.