Dataset Information

Prognostic and therapeutic implications of NHERF1 expression and regulation in colorectal cancer.

ABSTRACT:

Background

Na⁺ /H⁺ exchanger regulatory factor 1 (NHERF1) has been implicated in the tumorigenesis of several cancer types and is a potential therapeutic target. The current study evaluated the relationship between NHERF1 expression and clinical outcome in colorectal cancer (CRC).

Methods

NHERF1 expression was evaluated by immunohistochemistry in 167 patients with CRC primary tumors, 37 patients with no disease, and 27 patients with metastatic CRC (mCRC); and in the orthotopically implanted tumors in mice. NHERF1 expression was manipulated in CRC cells using inducible short hairpin RNAs to determine its biological functions.

Results

High expression of NHERF1 correlated with CRC progression and metastasis, as well as significantly worse overall survival, recurrence-free survival, and disease-specific survival. Orthotopic implantation studies demonstrated increased NHERF1 expression in liver metastases. Treatment of CRC xenografts with insulin-like growth factor 1 receptor (IGF1R) inhibitors downregulated NHERF1 expression, indicating NHERF1 is downstream of IGF1R signaling. Knockdown of NHERF1 increased apoptosis and reduced X-linked inhibitor of apoptosis protein (XIAP) and survivin expression, indicating NHERF1 is critical for CRC cell survival.

Conclusion

NHERF1 expression levels correlated with worse prognosis in patients with CRC and plays a critical role in CRC cell survival. Together, our findings establish NHERF1 as a novel potential marker for increased risk of CRC-specific mortality and identify NHERF1 as an attractive therapeutic target for mCRC treatment.

SUBMITTER: Leiphrakpam PD

PROVIDER: S-EPMC6996851 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Prognostic and therapeutic implications of NHERF1 expression and regulation in colorectal cancer.

Leiphrakpam Premila D PD Lazenby Audrey J AJ Chowdhury Sanjib S Smith Lynette M LM Mathiesen Michelle M Brattain Michael G MG Wang Jing J Black Jennifer D JD Are Chandrakanth C

Journal of surgical oncology 20191222 3

<h4>Background</h4>Na<sup>+</sup> /H<sup>+</sup> exchanger regulatory factor 1 (NHERF1) has been implicated in the tumorigenesis of several cancer types and is a potential therapeutic target. The current study evaluated the relationship between NHERF1 expression and clinical outcome in colorectal cancer (CRC).<h4>Methods</h4>NHERF1 expression was evaluated by immunohistochemistry in 167 patients with CRC primary tumors, 37 patients with no disease, and 27 patients with metastatic CRC (mCRC); and ...[more]

PMID: 31867736

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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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Dataset Information

Prognostic and therapeutic implications of NHERF1 expression and regulation in colorectal cancer.

Background

Methods

Results

Conclusion

Publications

Prognostic and therapeutic implications of NHERF1 expression and regulation in colorectal cancer.

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