Involvement of nuclear NHERF1 in colorectal cancer progression

Abstract

Abstract. NHERF1 (Na + /H + exchanger regulatory factor 1) is expressed in the luminal membrane 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 focused on the observation of the altered expression of NHERF1 from non-neoplastic tissues to 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 different localization and expression in the examined sites. The distant non-neoplastic tissues showed NHERF1 mostly expressed at the apical membrane, while in surrounding non-neoplastic tissue decreased the apical membrane and increased cytoplasmic immunoreactivity. In adenomas a shift from apical membrane to cytoplasmic localization and nuclear expression were observed. Cytoplasmic staining in the tumor, and metastatic sites was stronger than surrounding non-neoplastic tissue. Furthermore, nuclear NHERF1 expression was noted in 80% of all samples and surprisingly, it appeared already in adenoma lesions, suggesting that NHERF1 represents an early marker of pre-morphological triggering of colorectal carcinogenesis. Then, in few tumors a positive direct correlation between membrane NHERF1 and EGFR expression was evidenced by their colocalization. Nuclear NHERF1 expression, present in the early stages of carcinogenesis and related with poor prognosis, may contribute to the onset of malignant phenotype. Specifically, we hypothesize the direct involvement of nuclear NHERF1 in both carcinogenesis and progression and its role as a potential colorectal cancer marker. IntroductionColorectal cancer (CRC) is the second most common cause of cancer related death in the Western societies (1). At the time of diagnosis 19% of patients will present synchronous metastasis and 30-40% of patients will develop distant metachronous metastasis (2). The liver is one of the most common sites of metastasis and many molecular variables are still unclear. Some studies have suggested that the accumulation of specific alterations in cell growth genes are involved in cancer progression (3) and tumorigenesis (4). Thus, different gene expression can lead to unique transcriptional outcomes and consequently a multiple signalling pathways can be simultaneously activated. NHERF1 (Na + /H + exchanger regulatory factor 1, also named EBP50) is an adaptor protein that links several cellular receptors, ion transporters and other proteins to the plasma membrane of different types of cells (5-9). The association between specific growth factor receptors and NHERF1 has already been analysed (8-10) and indicates a critical role for this adaptor protein in growth factor signal transduction. Recently in normal cells, the level of NHERF1 expression has been demonstrated to have effects on the trafficking,...

The prognostic value of the Na+/H+ exchanger regulatory factor 1 (NHERF1) protein in cancer

“…Surprisingly, nuclear NHERF1 expression was noted in most samples, suggesting that nuclear NHERF1 expression represents an early marker of pre-morphological triggering of colorectal carcinogenesis.A positive direct correlation between membrane NHERF1 and EGFR expression was observed by their co-localization. The authors hypothesize that nuclear NHERF1 expression, present in the early stages of carcinogenesis and related with poor prognosis, might contribute to the onset of malignant phenotype [41]. Independently, Hayashi [22] and Mangia [41] envisage a potential role for NHERF1 as a marker in colorectal cancer.…”

“…The authors hypothesize that nuclear NHERF1 expression, present in the early stages of carcinogenesis and related with poor prognosis, might contribute to the onset of malignant phenotype [41]. Independently, Hayashi [22] and Mangia [41] envisage a potential role for NHERF1 as a marker in colorectal cancer.…”

NHERF1 regulates the progression of colorectal cancer through the interplay with VEGFR2 pathway

“…Other studies have showed that NHERF1 is considered a new player in colorectal cancer progression [26]. It has been reported that nuclear NHERF1 expression probably contributes to the malignant phenotype during the early stages of carcinogenesis [27, 28]. Also, cytoplasmic NHERF1 was higher in primary cancer than in adjacent normal mucosa, and tumors overexpressing NHERF1 were associated with nodal and distant metastases, poor grade and lymphovascular invasion (LVI) [29].…”

β-catenin interaction with NHERF1 and RASSF1A methylation in metastatic colorectal cancer patients

“…Hayashi et al [11] observed for the first time alterations of NHERF1 subcellular expression in CRC and have identified it as a new player in CRC progression. Our previous studies showed the expression and sub-localization of NHERF1 in different sites of metastatic CRC, suggesting a dynamic role of this protein in colon carcinogenesis [12, 13]. …”