NHERF1 – New Modifier of Colorectal Cancer Progression

Colorectal cancer (CRC) develops from multiple progressive modifications of normal intestinal epithelium into adenocarcinoma. Loss of cell polarity has been implicated as an early event in this process, but the molecular players involved are not well known. NHERF1 (Na+/H+ Exchanger Regulatory Factor 1) is an adaptor protein with apical membrane localization in polarized epithelia. In this study, we tested our hypothesis that NHERF1 plays a role in CRC. We examined surgical CRC resection specimens for changes in NHERF1 expression, and modeled these changes in two- and three-dimensional (2D and 3D) Caco-2 CRC cell systems. NHERF1 had significant alterations from normal to adenoma and carcinoma transitions (2=38.5, d.f.=4, P<0.001), displaying apical membrane localization in normal tissue but loss of expression in adenoma and ectopic overexpression in carcinoma. In Caco-2 cell models, NHERF1 depletion induced epithelial-mesenchymal-transition in 2D cell monolayers and disruption of apical-basal polarity in 3D cyst system. The mesenchymal phenotype of NHERF1-depleted cells was fully restored by re-expression of NHERF1 at the apical membrane. Cytoplasmic and nuclear NHERF1 re-expression not only failed to restore the epithelial phenotype but led to more aggressive phenotypes. Our findings suggest that membrane NHERF1 is an important regulator of epithelial morphogenesis, and that changes in NHERF1 expression correlate with CRC progression. NHERF1 loss and ectopic expression that induce massive disruption of epithelial cell polarity may, thereby, mark important steps in CRC development.