Transcriptional factor FOXO3 negatively regulates the expression of nm23-H1 in non-small cell lung cancer.
Transcriptional factor FOXO3 negatively regulates the expression of nm23-H1 in non-small cell lung cancer.
复制标题
转录因子 FOXO3 负向调节非小细胞肺癌 nm23-H1 的表达。
DOI：
10.1111/1759-7714.12260
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发表时间：
2016-01
期刊：
影响因子：
2.9
通讯作者：
Zhou Q
中科院分区：
文献类型：
--
作者：
Zhang L;Li L;Wei H;Guo L;Ai C;Xu H;Wu Z;Zhou Q
背景：Nm23‐H1是在大多数肿瘤模型中发现的第一个转移抑制因子，Nm23‐H1表达的降低或缺失与非小细胞肺癌的肿瘤进展和转移相关。尽管进行了广泛的研究，但nm23‐H1表达的调控机制还远未阐明。据报道，叉头盒转录因子（FOX）O3参与肿瘤生物学行为的多种调控信号通路。因此，我们旨在研究FOXO3活性与nm23‐H1表达之间的关系。方法：采用实时逆转录酶聚合酶链反应和Western blotting检测不同FOXO3质粒转染A549细胞后nm23‐H1信使核糖核酸和蛋白表达情况。双荧光素酶报告系统和染色质免疫沉淀法分别用于测定nm23‐H1基因启动子的活性和检测FOXO3与nm23‐H1启动子的结合。结果：激活的FOXO3降低了nm23‐H1的表达，显性阴性FOXO3增加了nm23‐H1的表达。FOXO3途径抑制剂对FOXO3活性的调节改变了nm23‐H1启动子活性。虽然在nm23‐H1启动子中存在一个假定的FOXO3结合位点，但FOXO3以间接方式调节nm23‐H1的表达。结论：FOXO3转录因子可降低非小细胞肺癌A549细胞系中肿瘤抑制基因nm23‐H1的表达水平，且nm23‐H1的表达水平受FOXO3间接调控。这一发现揭示了nm23‐H1的上游调控，并可能为抑制转移过程提供有希望的靶点。
Background: Nm23‐H1 was the first metastasis suppressor discovered in most tumor models and reduction or loss of nm23‐H1 expression correlates with tumor progression and metastasis in non‐small‐cell lung cancer. Despite extensive studies, the regulatory mechanism of nm23‐H1 expression is far from elucidated. The transcriptional factor forkhead box (FOX)O3 has been reported to be involved in multiple regulatory signaling pathways in the biological behavior of tumors. Therefore, we aimed to study the relationship between FOXO3 activity and nm23‐H1 expression. Methods: Real time reverse transcriptase‐polymerase chain reaction and Western blotting assays were employed to determine nm23‐H1 messenger ribonucleic acid and protein expression after being transformed by different FOXO3 plasmid in A549 cells. A dual luciferase reporter system and chromatin immunoprecipitation assay, were used to determine the promoter activity of the nm23‐H1 gene and to detect the binding of FOXO3 into the nm23‐H1 promoter, respectively. Results: We found that activated FOXO3 decreased nm23‐H1 expression and dominant negative FOXO3 increased nm23‐H1 expression. Modulation of FOXO3 activity with FOXO3 pathway inhibitors altered nm23‐H1 promoter activity. Although there is a putative binding site of FOXO3 in the nm23‐H1 promoter, FOXO3 regulated nm23‐H1 expression in an indirect manner. Conclusion: We demonstrated that the transcriptional factor FOXO3 decreased the expression levels of the tumor suppressor gene nm23‐H1 in the non‐small‐cell lung cancer A549 cell line and that the level of expression of nm23‐H1 was controlled by FOXO3 in an indirect manner. This finding provided an insight into the upstream regulation of nm23‐H1 and may provide promising targets for inhibition of the metastasis process.