Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota.
Cancer Res. 2016 Mar 1;76(5):1122-34. doi: 10.1158/0008-5472.CAN-15-1962. Epub 2015 Dec 23.
Metastasis is a major cause of death in patients with colorectal cancer, and increasing evidence supports the contribution of the epithelial-mesenchymal transition (EMT) to cancer progression. The dissociation of the E-cadherin/β-catenin adhesion complex represents a key step in EMT and promotes cancer invasion and metastasis, but the upstream signaling pathways regulating this interaction are poorly understood. Here, we show that PDLIM1, a member of the PDZ and LIM protein family, was downregulated in highly metastatic colorectal cancer cells and liver metastases from colorectal cancer patients. We found that loss of PDLIM1 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple colorectal cancer cell lines. Furthermore, PDLIM1 knockdown increased colon-derived liver metastasis in an orthotopic colorectal cancer model and promoted distant metastatic colonization in an experimental lung metastasis model. Mechanistic investigations revealed that PDLIM1 interacted with and stabilized the E-cadherin/β-catenin complex, thereby inhibiting the transcriptional activity of β-catenin and preventing EMT. Accordingly, PDLIM1 overexpression attenuated EMT of colorectal cancer cells. Moreover, the downregulation of PDLIM1 in colorectal cancer samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. In conclusion, our study demonstrates that PDLIM1 suppresses EMT and metastatic potential of colorectal cancer cells by stabilizing β-catenin at cell-cell junctions, and its loss in metastatic tissues may represent a potential prognostic marker of aggressive disease.
转移是结直肠癌患者死亡的主要原因，越来越多的证据支持上皮-间充质转化（EMT）对癌症进展的贡献。E-钙粘蛋白/β-连环蛋白黏附复合物的解离代表 EMT 的关键步骤，并促进癌症侵袭和转移，但调节这种相互作用的上游信号通路知之甚少。在这里，我们表明，PDLIM1 是 PDZ 和 LIM 蛋白家族的成员，在高度转移性结直肠癌细胞和结直肠癌患者的肝转移中下调。我们发现 PDLIM1 的缺失促进了 EMT 标志物的表达，并增加了多种结直肠癌细胞系的侵袭和迁移特性。此外，PDLIM1 敲低增加了结直肠来源的肝转移在原位结直肠癌模型中的发生，并促进了实验性肺转移模型中的远处转移定植。机制研究表明，PDLIM1 与 E-钙粘蛋白/β-连环蛋白复合物相互作用并稳定其，从而抑制 β-连环蛋白的转录活性并阻止 EMT。因此，PDLIM1 的过表达减弱了结直肠癌细胞的 EMT。此外，结直肠癌样本中 PDLIM1 的下调与 E-钙粘蛋白和膜β-连环蛋白水平降低相关，并与总生存期缩短相关。总之，我们的研究表明，PDLIM1 通过稳定细胞-细胞连接处的β-连环蛋白来抑制结直肠癌细胞的 EMT 和转移潜能，而转移组织中 PDLIM1 的缺失可能代表侵袭性疾病的潜在预后标志物。
