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NHERF1/EBP50 is a new marker in colorectal cancer.

ABSTRACT: Human colorectal cancer (CRC) arises from activating mutations in the Wnt/?-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 ?-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, ?-catenin nuclear translocation with elevation of Wnt/?-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.

SUBMITTER: Hayashi Y

PROVIDER: S-EPMC3003136 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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NHERF1/EBP50 is a new marker in colorectal cancer.

Hayashi Yuho Y Molina Jennifer R JR Hamilton Stanley R SR Georgescu Maria-Magdalena MM

Neoplasia (New York, N.Y.) 20101201 12

Human colorectal cancer (CRC) arises from activating mutations in the Wnt/β-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 β-catenin, undergoes successive alterations during the colorectal adenoma-to-carcinoma transition, ranging from loss of normal apical membrane distribution to ectopic cytoplasmic overexpressi ...[more]

PMID: 21170265

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Project description:Our purpose was to investigate whether Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) expression could be linked to prognosis in invasive breast carcinomas. NHERF1, an ezrin-radixin-moesin (ERM) binding phosphoprotein 50, is involved in the linkage of integral membrane proteins to the cytoskeleton. It is therefore believed to have an important role in cell signaling associated with changes in cell cytoarchitecture. NHERF1 expression is observed in various types of cancer and is related to tumor aggressiveness. To date the most extensive analyses of the influence of NHERF1 in cancer development have been performed on breast cancer. However, the underlying mechanism and its prognostic significance are still undefined. NHERF1 expression was studied by immunohistochemistry (IHC) in a cohort of 222 breast carcinoma patients. Association of cytoplasmic and nuclear NHERF1 expression with survival was analyzed. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Cytoplasmic NHERF1 expression was associated with negative progesterone receptor (PgR) (P=0.017) and positive HER2 expression (P=0.023). NHERF1 also showed a nuclear localization and this correlated with small tumor size (P=0.026) and positive estrogen receptor (ER) expression (P=0.010). Multivariate analysis identified large tumor size (P=0.011) and nuclear NHERF1 expression (P=0.049) to be independent prognostic variables for DFS. Moreover, the nuclear NHERF1(-)/ER(-) immunophenotype (27%) was statistically associated with large tumor size (P=0.0276), high histological grade (P=0.0411), PgR-negative tumors (P<0.0001) and high proliferative activity (P=0.0027). These patients had worse DFS compared with patients with nuclear NHERF1(+)/ER(+) tumors (75.4% versus 92.6%; P=0.010). These results show that the loss of nuclear NHERF1 expression is associated with reduced survival, and the link between nuclear NHERF1 and ER expression may serve as a prognostic marker for the routine clinical management of breast cancer patients.

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NHERF1/EBP50 is a new marker in colorectal cancer.

Publications

NHERF1/EBP50 is a new marker in colorectal cancer.

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