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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.
Highlights
Colorectal cancer is the third most common cancer in men and the second most common cancer in women worldwide, with an estimated incidence of more than 1.3 million in 2012, and mortality of 700,000 [1]
On the basis of the immunohistochemical staining on tissue microarrays composed of primary tumors and matched peritumoral tissues from 127 colorectal cancer patients, we found a similar pattern of distribution for PDLIM1, E-cadherin, and membrane b-catenin at the cell–cell junctions in normal mucosal tissues (Fig. 4D)
On the basis of the results derived from two cohorts of clinical samples, our study demonstrated that the expression of PDLIM1 was downregulated in colorectal cancer tissues compared with peritumoral tissues
Summary
Colorectal cancer is the third most common cancer in men and the second most common cancer in women worldwide, with an estimated incidence of more than 1.3 million in 2012, and mortality of 700,000 [1]. Despite various advances in the diagnosis and treatment of colorectal cancer over the past decades, the overall prognosis for patients with colorectal cancer remains poor [2]. Tumor metastasis is a significant factor in the management of colorectal cancer and is a major obstacle to successful treatment. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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