PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells
Hai-Ning Chen1, Kefei Yuan1, Na Xie1, Kui Wang1, Zhao Huang1, Yan Chen1,Qianhui Dou1, Min Wu2, Edouard C. Nice3,4, Zong-Guang Zhou1,*, and Canhua Huang1,*
Author Affiliations1Department 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.
2Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota.
3Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
4The State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China.↵*Corresponding Authors:
Canhua Huang, Sichuan University, No. 1 Keyuan 4 Road, Gaopeng St. High-Tech Zone, Chengdu, Sichuan 610041, China. Phone: 135-4065-1810; Fax: 86-28-8516-4060; E-mail:firstname.lastname@example.org; and Zong-Guang Zhou, E-mail: email@example.com
H.-N. Chen and K. Yuan contributed equally to this article.
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. Cancer Res; 76(5); 1122–34. ©2015 AACR.
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