Involvement of nuclear NHERF1 in colorectal cancer progression

NHERF1 (Na+/H+ exchanger regulatory factor 1) is expressed in the luminalmembrane of many epithelia, and associated with proteins involved in tumor progression.Alterations of NHERF1 expression in different sites of metastatic colorectal cancer(mCRC) suggest a dynamic role of this protein in colon carcinogenesis. We focusedon the observation of the altered expression of NHERF1 from non-neoplastic tissuesto metastatic sites by immunohistochemistry. Moreover, we studied, by immunofluorescence,the colocalization between NHERF1 and the epidermal growth factor receptor (EGFR),whose overexpression is implicated in CRC progression. NHERF1 showed a differentlocalization and expression in the examined sites. The distant non-neoplastictissues showed NHERF1 mostly expressed at the apical membrane, while in surroundingnon-neoplastic tissue decreased the apical membrane and increased cytoplasmicimmunoreactivity. In adenomas a shift from apical membrane to cytoplasmic localizationand nuclear expression were observed. Cytoplasmic staining in the tumor, and metastaticsites was stronger than surrounding non-neoplastic tissue. Furthermore, nuclearNHERF1 expression was noted in 80% of all samples and surprisingly, it appearedalready in adenoma lesions, suggesting that NHERF1 represents an early markerof pre-morphological triggering of colorectal carcinogenesis. Then, in few tumorsa positive direct correlation between membrane NHERF1 and EGFR expression wasevidenced by their colocalization. Nuclear NHERF1 expression, present in the earlystages of carcinogenesis and related with poor prognosis, may contribute to theonset of malignant phenotype. Specifically, we hypothesize the direct involvementof nuclear NHERF1 in both carcinogenesis and progression and its role as a potentialcolorectal cancer marker.