Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan.
Oncogene. 2012 May 10;31(19):2389-400. doi: 10.1038/onc.2011.419. Epub 2011 Sep 26.
We integrated four gene expression profile data sets, namely two different pair-matched stage I lung adenocarcinoma data sets, secondary metastatic tumors vs benign tumors and lung tumor metastasizes to the brain, and we identified one kinase, T-LAK Cell-Originated Protein Kinase (TOPK), as a putative gene that promotes metastasis. To delineate the role of TOPK in lung cancer, we showed that overexpression of TOPK, but not a catalytically inactive form of TOPK, can enhance the migration and invasion of lung fibroblasts or cells with low TOPK expression. In addition, TOPK-induced cell migration was shown to be a PI3K/AKT-dependent event. TOPK concurrently promoted AKT phosphorylation at Ser(473) and decreased the phosphatase and tensin homolog (PTEN) levels, whereas TOPK knockdown had the reverse effects. LY294002, a PI3K inhibitor, did not inhibit the TOPK-induced decrease in PTEN, and co-expression of PTEN significantly reduced TOPK-induced AKT phosphorylation in a dose-dependent manner; these results indicate that the TOPK-mediated PTEN decrease has an upstream role in regulating PI3K/AKT-stimulated migration. Using immunohistochemical analysis of lung cancer tissue samples, we showed that a high TOPK expression level correlates strongly with reduced overall and disease-free survivals. Moreover, an inverse correlation between TOPK and PTEN expression was present and is consistent with the biochemical findings. Finally, a combination of high TOPK and low PTEN expression was inversely correlated with overall and disease-free survivals, independent of other pathologic staging factors. Our results suggest that TOPK is a potential therapeutic target in lung cancer that promotes cell migration by modulating a PI3K/PTEN/AKT-dependent signaling pathway; they also suggest that high TOPK expression, either alone or in combination with a low level of PTEN, may serve as a prognostic marker for lung cancer.
我们整合了四个基因表达谱数据集，即两个不同配对的 I 期肺腺癌数据集、继发性转移性肿瘤与良性肿瘤和肺肿瘤转移到大脑，并确定了一个激酶，T-LAK 细胞起源蛋白激酶（TOPK），作为一个潜在的促进转移的基因。为了描绘 TOPK 在肺癌中的作用，我们表明 TOPK 的过表达，而不是 TOPK 的无催化活性形式，可以增强肺成纤维细胞或低 TOPK 表达细胞的迁移和侵袭。此外，TOPK 诱导的细胞迁移是 PI3K/AKT 依赖性事件。TOPK 同时促进 AKT 在 Ser(473)的磷酸化，并降低磷酸酶和张力蛋白同源物（PTEN）的水平，而 TOPK 敲低则有相反的效果。PI3K 抑制剂 LY294002 不能抑制 TOPK 诱导的 PTEN 减少，而 PTEN 的共表达以剂量依赖性方式显著降低 TOPK 诱导的 AKT 磷酸化；这些结果表明，TOPK 介导的 PTEN 减少在调节 PI3K/AKT 刺激的迁移中起上游作用。通过对肺癌组织样本的免疫组织化学分析，我们表明高 TOPK 表达水平与总生存率和无病生存率的降低密切相关。此外，TOPK 和 PTEN 表达之间存在负相关，与生化发现一致。最后，高 TOPK 和低 PTEN 表达的组合与总生存率和无病生存率呈负相关，与其他病理分期因素无关。我们的研究结果表明，TOPK 是肺癌的一个潜在治疗靶点，通过调节 PI3K/PTEN/AKT 依赖性信号通路促进细胞迁移；它们还表明，高 TOPK 表达，无论是单独存在还是与低水平的 PTEN 结合，都可能作为肺癌的预后标志物。
