title: PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial-Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells.
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.
authors.affiliation: 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.
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Kefei
authors.initials: K
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Na
authors.initials: N
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Qianhui
authors.initials: Q
authors.lastname: Dou
authors.affiliation: Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. The State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China.
authors.forename: Edouard C
authors.initials: EC
authors.lastname: Nice
authors.affiliation: 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. hcanhua@scu.edu.cn zhou767@163.com.
authors.forename: Zong-Guang
authors.initials: ZG
authors.lastname: Zhou
authors.affiliation: 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. hcanhua@scu.edu.cn zhou767@163.com.
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000737:chemistry*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D060588:LIM Domain Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055550:Protein Stability; D014157:Transcription Factors / Q000502:physiology*; D051176:beta Catenin / Q000737:chemistry*
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; C484572:LDB2 protein, human; D060588:LIM Domain Proteins; D014157:Transcription Factors; D051176:beta Catenin