Division of Pathology, Nottingham University, Nottingham, UK.
Oncogene. 2011 Jun 30;30(26):2997-3002. doi: 10.1038/onc.2011.26. Epub 2011 Feb 21.
CTEN/TNS4 is an oncogene in colorectal cancer (CRC), which can induce cell motility although its mechanistic basis of activity and the clinical implications of Cten expression are unknown. As Cten is in complex with integrins at focal adhesions, we hypothesised that it may interact with integrin-linked kinase (ILK). Through forced expression and knockdown of Cten in HCT116 and SW620 (respectively, showing low and high Cten expression), we showed that Cten could regulate ILK. However, inhibition of ILK after forced expression of Cten abrogated the motility-inducing effects of Cten, thereby demonstrating that the Cten-ILK interaction was functionally relevant. Combined knockdown of Cten and ILK had no additive effects on cell motility compared with knockdown of each individually. In order to investigate the clinical implications of Cten expression, a series of 462 CRCs were evaluated by immunohistochemistry. High expression of Cten was associated with advanced Dukes' stage (P<0.001), poor prognosis (P<0.001) and distant metastasis (P=0.008). The role of Cten in metastasis was tested by (a) intrasplenic injection of CRC cells stably transfected with a Cten expression vector into nude mice and (b) testing a series of primary human CRCs and their metastases by immunohistochemistry. Compared with controls, mice injected with cells expressing Cten developed larger tumours in the spleen (P<0.05) and liver (P<0.05). In the human cases, compared with primary tumours, the metastatic deposits had a significantly higher frequency of nuclear localisation of Cten (P=0.002). We conclude that Cten expression is of prognostic significance in CRC, and we delineate a Cten-ILK pathway controlling cell motility and possibly promoting metastasis.
CTEN/TNS4 是结直肠癌（CRC）中的一种癌基因，它可以诱导细胞运动，尽管其活性的机制基础和 Cten 表达的临床意义尚不清楚。由于 Cten 与粘着斑处的整合素复合物，我们假设它可能与整合素连接激酶（ILK）相互作用。通过在 HCT116 和 SW620 中强制表达和敲低 Cten（分别表现为低表达和高表达 Cten），我们表明 Cten 可以调节 ILK。然而，在强制表达 Cten 后抑制 ILK 会消除 Cten 诱导运动的作用，从而表明 Cten-ILK 相互作用具有功能相关性。与单独敲低每个基因相比，Cten 和 ILK 的联合敲低对细胞运动没有附加作用。为了研究 Cten 表达的临床意义，我们通过免疫组化评估了一系列 462 例 CRC。Cten 的高表达与晚期 Dukes 分期（P<0.001）、不良预后（P<0.001）和远处转移（P=0.008）相关。通过（a）将稳定转染 Cten 表达载体的 CRC 细胞经脾内注射到裸鼠中以及（b）通过免疫组化检测一系列原发性 CRC 及其转移瘤，检测了 Cten 在转移中的作用。与对照组相比，注射表达 Cten 的细胞的小鼠在脾脏（P<0.05）和肝脏（P<0.05）中形成更大的肿瘤。在人类病例中，与原发性肿瘤相比，转移灶中 Cten 的核定位频率显著更高（P=0.002）。我们得出结论，Cten 表达在 CRC 中具有预后意义，我们描绘了一条控制细胞运动并可能促进转移的 Cten-ILK 通路。
