Overexpression of nuclear NHERF1 in advanced colorectal cancer: Association with hypoxic microenvironment and tumor invasive phenotype

Malfettone, Andrea; Silvestris, Nicola; Paradiso, Angelo; Mattioli, Eliseo; Simone, Giovanni de; Mangia, Anita

doi:10.1016/j.yexmp.2012.03.004

Cited by 41 publications

(48 citation statements)

References 29 publications

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“…In previous studies, we showed an upregulation of this protein by hypoxia in breast cancer and a significant association between NHERF1 and HIF-1a in colorectal cancer. [26][27][28] It is possible that these differences derived from different histological subtypes or the small sample size.…”

Section: Discussionmentioning

confidence: 99%

“…26,39,40 More importantly, it was demonstrated that its overexpression is significantly correlated with poor prognosis in particular in breast and colon cancers, and could be helpful in predicting the aggressiveness of the disease. 26,27,[40][41][42] Previous studies have shown that NHERF1 is involved in various Abbreviations: cP-gp, cytoplasmic P-gp; mP-gp, membranous P-gp; cHIF-1a, cytoplasmic HIF-1a; nHIF-1a, nuclear HIF-1a; cSR1, cytoplasmic SR1. P values were calculated with the Fisher's exact test.…”

Section: Discussionmentioning

confidence: 99%

“…In breast and colorectal cancers, we found that NHERF1 expression is increased by low oxygen tension, providing a direct functional link between the hypoxic and acidic tumor microenvironment. 26,27 The strong correlation of NHERF1 with HIF-1a also showed an association with increased tumor cell aggressiveness. 28 In addition, Karn and coworkers 29 demonstrated that NHERF1 expressing breast cancers have a greater risk of developing resistance to endocrine therapy.…”

Section: Introductionmentioning

confidence: 95%

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The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

Mangia

Caldarola

Dell'Endice

et al. 2015

Cancer Biology & Therapy

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Cellular resistance in advanced gastric cancer (GC) might be related to function of multidrug resistance (MDR) proteins. The adaptor protein NHERF1 (Na C /H C exchanger regulatory factor) is an important player in cancer progression for a number of solid malignancies, even if its role to develop drug resistance remains uncertain. Herein, we aimed to analyze the potential association between NHERF1 expression and P-gp, sorcin and HIF-1a MDR-related proteins in advanced GC patients treated with epirubicin/oxaliplatin/capecitabine (EOX) chemotherapy regimen, and its relation to response. Total number of 28 untreated patients were included into the study. Expression and subcellular localization of all proteins were assessed by immunohistochemistry on formalin-fixed paraffin embedded tumor samples. We did not found significant association between NHERF1 expression and the MDR-related proteins. A trend was observed between positive cytoplasmic NHERF1 (cNHERF1) expression and negative nuclear HIF-1a (nHIF-1a) expression (68.8% versus 31.3% respectively, P D 0.054). However, cytoplasmic P-gp (cP-gp) expression was positively correlated with both cHIF-1a and sorcin expression (P D 0.011; P D 0.002, respectively). Interestingly, nuclear NHERF1 (nNHERF1) staining was statistically associated with clinical response. In detail, 66.7% of patients with high nNHERF1 expression had a disease control rate, while 84.6% of subjects with negative nuclear expression of the protein showed progressive disease (P D 0.009). Multivariate analysis confirmed a significant correlation between nNHERF1 and clinical response (OR 0.06, P D 0.019). These results suggest that nuclear NHERF1 could be related to resistance to the EOX regimen in advanced GC patients, identifying this marker as a possible independent predictive factor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

Mangia

Caldarola

Dell'Endice

et al. 2015

Cancer Biology & Therapy

Self Cite

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“…Interestingly, NHERF1 can be highly expressed in the cytoplasm in a subset of CRCs [14] and in the nucleus in invasive CRC fronts [15]. Cytoplasmic expression of NHERF1 increases cell proliferation [14].…”

Section: Introductionmentioning

confidence: 99%

NHERF1/EBP50 Suppresses Wnt-β-Catenin Pathway–Driven Intestinal Neoplasia

2016

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NHERF1/EBP50, an adaptor molecule that interacts with β-catenin, YAP, and PTEN, has been recently implicated in the progression of various human malignancies, including colorectal cancer. We report here that NHERF1 acts as a tumor suppressor in vivo for intestinal adenoma development. NHERF1 is highly expressed at the apical membrane of mucosa intestinal epithelial cells (IECs) and serosa mesothelial cells. NHERF1-deficient mice show overall longer small intestine and colon that most likely could be attributed to a combination of defects, including altered apical brush border of absorbtive IECs and increased number of secretory IECs. NHERF1 deficiency in ApcMin/+ mice resulted in significantly shorter animal survival due to markedly increased tumor burden. This resulted from a moderate increase of the overall tumor density, more pronounced in females than males, and a massive increase in the number of large adenomas in both genders. The analysis of possible pathways controlling tumor size showed upregulation of Wnt-β-catenin pathway, higher expression of unphosphorylated YAP, and prominent nuclear expression of cyclin D1 in NHERF1-deficient tumors. Similar YAP changes, with relative decrease of phosphorylated YAP and increase of nuclear YAP expression, were observed as early as the adenoma stages in the progression of human colorectal cancer. This study discusses a complex role of NHERF1 for intestinal morphology and presents indisputable evidence for its in vivo tumor suppressor function upstream of Wnt-β-catenin and Hippo-YAP pathways.

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“…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]. It was also reported that expression of NHERF1 was strongly correlated with expression of HIF1α and VEGFRs both in breast cancer and lymphatic metastastic colorectal cancer [30, 31], indicating that NHERF1 expression might be involved in metastatic progression by regulating the cell adaptive changes to the tumor microenvironment. However, the mechanism of NHERF1 up-regulation in cancers and the contribution of NHERF1 to the regulation in the metastatic progression were still unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Hao

et al. 2016

Oncotarget

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The oncogenic role of ectopic expression of Na+/H+ exchanger regulatory factor 1 (NHERF1) was recently suggested in colorectal cancer, where it was implicated in playing a role in the tumor hypoxia microenvironment. Here we showed that a high level expression of NHERF1 was found in colorectal cancer tissues and that the expression of NHERF1 was positively correlated with VEGFR2 expression. The prognostic value of VEGFR2 expression in colorectal cancer relied on the expression of NHERF1. The up-regulation of NHERF1 induced by the exposure to hypoxia in colon cancer cells depended on the activation of VEGFR2 signaling. NHERF1 in turn inhibited the activation of VEGFR2 signaling which could be regulated by the interaction between NHERF1 and VEGFR2, resulting in the reduction of migration and invasion of colon cancer cells. These results suggest a dynamic interplay between NHERF1 and VEGFR2 signaling in colorectal cancer, which could explain the contribution of NHERF1 to the regulation of tumor cell responses to the hypoxia microenvironment.

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Overexpression of nuclear NHERF1 in advanced colorectal cancer: Association with hypoxic microenvironment and tumor invasive phenotype

Cited by 41 publications

References 29 publications

The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

NHERF1/EBP50 Suppresses Wnt-β-Catenin Pathway–Driven Intestinal Neoplasia

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

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