PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells
PUBLISHED: 2016-04-13  785 total views, 1 today

Hai-Ning Chen1Kefei Yuan1Na Xie1Kui Wang1Zhao Huang1Yan Chen1,Qianhui Dou1Min Wu2Edouard C. Nice3,4Zong-Guang Zhou1,*, and Canhua Huang1,*

Author Affiliations

1Department 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:hcanhua@scu.edu.cn; and Zong-Guang Zhou, E-mail: zhou767@163.com

H.-N. Chen and K. Yuan contributed equally to this article.

Abstract

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.

The copyright reseverd by Cancer Res; 76(5); 1122–34. ©2015 AACR. Please log on Cancer Res to view the full text.http://cancerres.aacrjournals.org/content/76/5/1122.abstract

Author
Dr. Huang Canhua
+ Author Profile

Dr.Huang Canhua

Professor, Doctorial tutor

State Key Laboratory of Biotherapy, SichuanUniversity

 

Expertise:

The screening of drug targets with systembiology.

Molecular mechanism of virus-inducedcarcinogenesis.

 

Experienceand Award

Postdoctoral research in the Department ofBiology, National University of Singapore. 

Served as Research Scientist in CancerInstitute of the National University of Singapore in 2003. Returned and hold aposition of State Key Laboratory professor in Sichuan University since 2005.

Winner of National Outstanding YouthScience Foundation. 

Chief scientist of major national scientific researchproject "Virus-induced tumorigenesis oxidation reduction proteomeresearch". 

Yangtze River scholar Professor of the Ministry of Education. 


Email: hcanhua@scu.edu.cn

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