Department of Urology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Clin Cancer Res. 2010 Dec 1;16(23):5654-63. doi: 10.1158/1078-0432.CCR-10-0376.
Invasion and metastasis are key steps in the progression of urothelial cancer (UC) into a critical disease. Foxo3a is a member of the Foxo transcription factor family that modulates the expression of various genes. We aimed to elucidate the role of Foxo3a in UC invasion.
Foxo3a mRNA and protein expressions in UC samples were investigated by gene expression assays and immunohistochemistry, respectively. Foxo3a expression was compared with clinicopathologic characteristics and patient prognoses based on UC samples. Quantitative real-time polymerase chain reaction, Western blotting, and migration assays were also conducted in UC cells.
Foxo3a expression decreased in invasive UC; patients with low Foxo3a expression had poor disease-free survival, cancer-specific survival, and overall survival; Foxo3a knockdown in UC cells increased cellular motility. Foxo3a negatively regulated Twist1 and Y-box-binding protein 1 (YB-1), and positively regulated E-cadherin in KK47 and TCCsup cells that expressed Twist1, but not in T24 cells that did not express Twist1. Foxo3a-associated acetyltransferase p300 and Foxo3a acetylation status also affected UC motility.
The results of this study indicate that Foxo3a regulates motility of UC through negative regulation of Twist1 and YB-1, and through positive regulation of E-cadherin. This suggests that Foxo3a could act as an independent prognostic factor in UC and could represent a promising molecular target for cancer therapeutics.
浸润和转移是膀胱癌（UC）发展为致命疾病的关键步骤。Foxo3a 是 Foxo 转录因子家族的成员，可调节多种基因的表达。我们旨在阐明 Foxo3a 在 UC 浸润中的作用。
通过基因表达分析和免疫组织化学分别检测 UC 样本中 Foxo3a mRNA 和蛋白的表达。根据 UC 样本，将 Foxo3a 表达与临床病理特征和患者预后进行比较。还在 UC 细胞中进行了定量实时聚合酶链反应、Western blot 和迁移分析。
Foxo3a 在浸润性 UC 中表达降低；Foxo3a 低表达的患者无病生存率、癌症特异性生存率和总生存率较差；在表达 Twist1 的 KK47 和 TCCsup 细胞中，Foxo3a 敲低会增加细胞迁移能力，但在不表达 Twist1 的 T24 细胞中则不会。Foxo3a 负调控 Twist1 和 Y 框结合蛋白 1（YB-1），并在表达 Twist1 的 KK47 和 TCCsup 细胞中正向调控 E-钙黏蛋白，但在不表达 Twist1 的 T24 细胞中则没有。Foxo3a 相关乙酰转移酶 p300 和 Foxo3a 乙酰化状态也影响 UC 的迁移能力。
本研究结果表明，Foxo3a 通过负调控 Twist1 和 YB-1 以及通过正调控 E-钙黏蛋白来调节 UC 的运动能力。这表明 Foxo3a 可作为 UC 的独立预后因素，并可能成为癌症治疗的有前途的分子靶标。
