Clinical Implications of the Influence of Ehm2 on the Aggressiveness of Breast Cancer Cells through Regulation of Matrix Metalloproteinase-9 Expression

Yu, Hefen; Ye, Lin; Mansel, Robert Edward; Zhang, Yuxiang; Jiang, Wen Guo

doi:10.1158/1541-7786.mcr-10-0186

Cited by 18 publications

(20 citation statements)

References 39 publications

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“…Interestingly, Ehm2 is overexpressed in breast, prostate, and skin cancer (76)(77)(78). Ehm2 overexpression correlates with a high metastatic potential and poor prognosis (78). These studies may seem in contradiction with our data showing that Ehm2 is important for epithelial cell morphology and cohesion and acts downstream of CRB3A to limit migration.…”

Section: Discussioncontrasting

confidence: 77%

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CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling

Loie

Charrier

Sollier

et al. 2015

Molecular and Cellular Biology

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The transmembrane protein CRB3A controls epithelial cell polarization. Elucidating the molecular mechanisms of CRB3A function is essential as this protein prevents the epithelial-to-mesenchymal transition (EMT), which contributes to tumor progression. To investigate the functional impact of altered CRB3A expression in cancer cells, we expressed CRB3A in HeLa cells, which are devoid of endogenous CRB3A. While control HeLa cells display a patchy F-actin distribution, CRB3A-expressing cells form a circumferential actomyosin belt. This reorganization of the cytoskeleton is accompanied by a transition from an ameboid cell shape to an epithelial-cell-like morphology. In addition, CRB3A increases the cohesion of HeLa cells. To perform these functions, CRB3A recruits p114RhoGEF and its activator Ehm2 to the cell periphery using both functional motifs of its cytoplasmic tail and increases RhoA activation levels. ROCK1 and ROCK2 (ROCK1/2), which are critical effectors of RhoA, are also essential to modulate the cytoskeleton and cell shape downstream of CRB3A. Overall, our study highlights novel roles for CRB3A and deciphers the signaling pathway conferring to CRB3A the ability to fulfill these functions. Thereby, our data will facilitate further investigation of CRB3A functions and increase our understanding of the cellular defects associated with the loss of CRB3A expression in cancer cells.T he physiology of epithelial cells relies on the asymmetric distribution of specific cellular constituents-a structural organization referred to as epithelial polarity (1). Epithelial cell polarization results in the regionalization of the plasma membrane into apical, lateral, and basal domains. In vertebrate epithelial cells, the apical and lateral domains are segregated by tight junctions (TJ), which seal the intercellular space to prevent passive diffusion across the tissue (2). Different groups of apical and lateral proteins cooperate within their respective domains to elaborate membrane territories with specific compositions and functions (3). In addition, the mutual antagonism between apical and lateral protein complexes defines a sharp apicolateral boundary (3). Pioneer studies in Drosophila melanogaster have established that one of these protein complexes is articulated around the transmembrane apical protein Crumbs (Crb) (4-7). The mammalian genome encodes three Crb orthologs, namely, CRB1, CRB2, and CRB3 (8). CRB1 is expressed mainly in the brain, cornea, and retina (9, 10). Mutations in the human CRB1 or mouse Crb1 gene cause retinal dystrophies (11)(12)(13)(14). CRB2 distribution overlaps that of CRB1, but CRB2 is also found in other organs such as kidneys (15). CRB2 is required for retinal integrity and for gastrulation of mouse embryos (16, 17). CRB3 is widely expressed in epithelial tissues and exists as two isoforms, namely, CRB3A and CRB3B (18,19). The latter associates with spindle poles during mitosis or is found in the primary cilium of epithelial cells to control cytokinesis and ciliogenesis (19). CRB3A is apical...

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Section: Discussioncontrasting

confidence: 77%

“…Of note, Ehm2 is an essential component of this signaling pathway. Interestingly, Ehm2 is overexpressed in breast, prostate, and skin cancer (76)(77)(78). Ehm2 overexpression correlates with a high metastatic potential and poor prognosis (78).…”

Section: Discussionmentioning

confidence: 99%

CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling

Loie

Charrier

Sollier

et al. 2015

Molecular and Cellular Biology

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“…It also promotes ovarian tumor growth and drug resistance (37). How EPB41L4B might relate to cancer is unclear, but Ehm2, a member of the NF2/ERM/4.1 superfamily, has been implicated in breast and prostate cancer invasiveness (38, 39). Thus, beyond biomarker use, these genes might also contribute to RMS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group

Hingorani

Missiaglia

Shipley

et al. 2015

Clinical Cancer Research

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Purpose Pediatric rhabdomyosarcoma has two common histological subtypes: embryonal (ERMS) and alveolar (ARMS). PAX/FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology while fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion-gene negative RMS (FN-RMS) patients but this has not been independently validated. The goal of the current study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS. Experimental Design Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathological characteristics as well as overall and event-free survival. Results MG5 standardized score showed no significant association with any of the available clinical-pathological variables. The MG5 signature score showed a significant correlation with overall (N=57; HR 7.3 95%CI[1.9-27.0], p=0.003) and failure-free survival (N=57; HR 6.1 95%CI[1.9-19.7], p=0.002). Conclusions This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk-stratification in future, prospective clinical trial.

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“…Gelatin zymography assay. The activities of MMPs were assayed as previously described (14). The cells were seeded into tissue culture flasks at a density of 1x10 6 cells.…”

Section: Methodsmentioning

confidence: 99%

“…The overexpression of Ehm2 can promote prostate cancer progression and metastasis (13). The expression of Ehm2 is also elevated in breast cancers, which is associated with metastasis and a poor prognosis of patients with the disease (14). The knockdown of Ehm2 in MCF-7 cells has been shown to not only increase apoptosis, but also to reduce invasiveness through a regulation of matrix metalloproteinase (MMP)9 (14).…”

Section: Introductionmentioning

confidence: 99%

Differential expression and functions of Ehm2 transcript variants in lung adenocarcinoma

Yang

et al. 2019

Int J Oncol

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Ehm2 [also known as erythrocyte membrane protein band 4.1-like protein 4B (EPB41L4B)] is a member of the NF2/ERM/4.1 superfamily. The overexpression of Ehm2 has been observed in metastatic cancer cells. Through alternative splicing, the Ehm2 gene produces two transcript variants that encode the two different isoforms, Ehm2/1 and Ehm2/2. The biological functions of these different Ehm2 transcript variants remain unclear. The present study aimed to determine the expression of the Ehm2 variants in lung adenocarcinoma and their involvement in the disease progression of the patients. The expression of Ehm2 transcript variants in human lung adenocarcinoma tissues was analyzed using immunohistochemistry and western blot analysis. Ehm2 variants were overexpressed or knocked down in A549 human lung adenocarcinoma cells. The consequent effects of the genetic modifications on the cellular functions of lung cancer cells were then examined using in vitro cell viability, invasion and migration assays. The expression of epithelial-mesenchymal transition (EMT)-related markers was evaluated by western blot analysis in the cell models. The association of Ehm2 variant expression with patient survival was analyzed using Kaplan-Meier survival analysis. The expression of Ehm2/1 was significantly decreased in lung cancers compared with the paired normal lung tissues (P<0.05), while the Ehm2/2 protein levels were higher in the tumors than in the paired normal lung tissues, although this was not statistically significant. The overexpression of Ehm2/1 exerted inhibitory effects, while the knockdown of Ehm2/1 promoted the growth, invasion and migration of A549 cells in vitro. Ehm2/2 was expressed at low levels in the A549 cells and the enforced expression of Ehm2/2 significantly increased the invasiveness and migration of the A549 cells. Immunofluorescence staining revealed that Ehm2/1 was confined to the plasma membrane, while Ehm2/2 was observed at both the plasma membrane and cytoplasm. The overexpression of Ehm2/1 resulted in the upregulation of the epithelial marker, E-cadherin, and in the decreased expression of the mesenchymal markers, N-cadherin and Snail1, while the knockdown of Ehm2/1 and the enforced expression of Ehm2/2 had the opposite effects on the protein levels of EMT-related markers. Kaplan-Meier survival analysis revealed that higher Ehm2/1 transcript levels were associated with the longer survival of patients with lung adenocarcinoma, while the lower expression of Ehm2/2 exhibited a similar association with patient survival. Taken together, the two Ehm2 variants appear to be differentially expressed in lung adenocarcinoma. Ehm2/1 may function as a putative tumor suppressor in the disease progression of lung adenocarcinoma, while Ehm2/2 may have an opposite function.

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Clinical Implications of the Influence of Ehm2 on the Aggressiveness of Breast Cancer Cells through Regulation of Matrix Metalloproteinase-9 Expression

Cited by 18 publications

References 39 publications

CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling

CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group

Differential expression and functions of Ehm2 transcript variants in lung adenocarcinoma

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