NHERF1/EBP50 Is a New Marker in Colorectal Cancer

Human colorectal cancer (CRC) arises from activating mutations in the Wnt/beta-catenin pathway that converge with additional molecular changes to shape tumor development and patient prognosis. We report here that Na+/H+ exchanger 3 regulating factor 1 (NHERF1)/EBP50, an adaptor molecule that interacts with beta-catenin, undergoes successive alterations during the colorectal adenoma-to-carcinoma transition, ranging from loss of normal apical membrane distribution to ectopic cytoplasmic overexpression. NHERF1 depletion in human intestinal epithelial polarized cells induced epithelial-mesenchymal transition, beta-catenin nuclear translocation with elevation of Wnt/beta-catenin transcriptional targets, and increased cell migration and invasion. Ectopic cytoplasmic NHERF1 expression additionally intensified the transformed phenotype by increasing cell proliferation. The epithelial morphology and reduced cell motility could only be restored by re-expression of NHERF1 specifically at the apical plasma membrane. We conclude that alterations in the apical membrane localization of NHERF1 contribute to CRC through the disruption of epithelial morphology. This study identifies NHERF1 as a new player in CRC progression and supports the notion that the expression or subcellular distribution of NHERF1 may be used as diagnostic marker for CRC.