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Journal ArticleDOI

Prognostic Implication of Ezrin Overexpression in Myxofibrosarcomas

29 Jun 2010-Annals of Surgical Oncology (Springer-Verlag)-Vol. 17, Iss: 12, pp 3212-3219
TL;DR: In primary myxofibrosarcomas, ezrin overexpression correlates with important prognostic elements and independently portends worse outcomes, highlighting the potential prognostic usefulness of eZrin in predicting tumor aggressiveness.
Abstract: Background The bases of tumorigenesis, progression, and metastasis remain obscure in myxofibrosarcoma. As a member of ezrin-radixin-moesin family, ezrin acts as a link between the cell membrane and actin cytoskeleton to integrate cell adhesion–mediated signaling. It is implicated in tumor progression and metastatic dissemination, and it is associated with adverse outcomes in several cancer types, including pediatric sarcomas.
Citations
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Journal ArticleDOI
TL;DR: Findings highlight ASS1 as a novel tumor suppressor in myxofibrosarcomas, with loss of expression linked to promoter methylation, clinical aggressiveness, and sensitivity to ADI-PEG20.
Abstract: Purpose: The principal goals were to identify and validate targetable metabolic drivers relevant to myxofibrosarcoma pathogenesis using a published transcriptome. Experimental Design: As the most significantly downregulated gene regulating amino acid metabolism, argininosuccinate synthetase ( ASS1) was selected for further analysis by methylation-specific PCR, pyrosequencing, and immunohistochemistry of myxofibrosarcoma samples. The roles of ASS1 in tumorigenesis and the therapeutic relevance of the arginine-depriving agent pegylated arginine deiminase (ADI-PEG20) were elucidated in ASS1-deficient myxofibrosarcoma cell lines and xenografts with and without stable ASS1 reexpression. Results: ASS1 promoter hypermethylation was detected in myxofibrosarcoma samples and cell lines and was strongly linked to ASS1 protein deficiency. The latter correlated with increased tumor grade and stage and independently predicted a worse survival. ASS1-deficient cell lines were auxotrophic for arginine and susceptible to ADI-PEG20 treatment, with dose-dependent reductions in cell viability and tumor growth attributable to cell-cycle arrest in the S-phase. ASS1 expression was restored in 2 of 3 ASS1-deficient myxofibrosarcoma cell lines by 5-aza-2′-deoxycytidine, abrogating the inhibitory effect of ADI-PEG20. Conditioned media following ASS1 reexpression attenuated HUVEC tube-forming capability, which was associated with suppression of MMP-9 and an antiangiogenic effect in corresponding myxofibrosarcoma xenografts. In addition to delayed wound closure and fewer invading cells in a Matrigel assay, ASS1 reexpression reduced tumor cell proliferation, induced G 1 -phase arrest, and downregulated cyclin E with corresponding growth inhibition in soft agar and xenograft assays. Conclusions: Our findings highlight ASS1 as a novel tumor suppressor in myxofibrosarcomas, with loss of expression linked to promoter methylation, clinical aggressiveness, and sensitivity to ADI-PEG20. Clin Cancer Res; 19(11); 2861–72. ©2013 AACR .

122 citations


Cites methods from "Prognostic Implication of Ezrin Ove..."

  • ...Immunohistochemistry Tissue microarray (TMA) sections were prepared for antigen retrieval as described (4, 26, 28), encompassing all cases subjected tomethylation-specific PCR....

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  • ...The criteria for the diagnosis and parameter assessment were previously elaborated (1, 4, 26)....

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Journal ArticleDOI
TL;DR: The results demonstrated that downregulation of ezrin reduced β-catenin and increased E-cadherin at the protein level but had no effects on their mRNA levels, suggesting posttranscriptional regulation of these two adhesion molecules.
Abstract: Ezrin, one of the ezrin–radixin–moesin proteins, is involved in the formation of cell membrane processes such as lamellipodia and filopodia and acts as a membrane–cytoskeleton linker. Its aberrant expression correlates with development and progression of several human cancers. However, the expression of ezrin and its role in lung cancer are currently unknown. In this study, we performed ezrin small interfering RNA transfection in two lung cancer cell lines and examined the effects on malignant phenotypes in cancer cells by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, and chamber transwell assays. Ezrin knockdown significantly reduced the proliferation, migration, and invasion of lung cancer cells in vitro. To address the possible mechanisms, we evaluated the expression of adhesion molecules E-cadherin and β-catenin by Western blot and reverse transcriptase-polymerase chain reaction analyses. The results demonstrated that downregulation of ezrin reduced β-catenin and increased E-cadherin at the protein level but had no effects on their mRNA levels, suggesting posttranscriptional regulation of these two adhesion molecules. Immunofluorescence assays revealed that ezrin knockdown restored membranous expression of E-cadherin and decreased cytoplasmic β-catenin in lung cancer cells. In addition, ezrin expression was immunohistochemically evaluated on 135 normal and 183 lung cancer tissues. The expression of ezrin was significantly higher in cancer samples than paired autologous normal lung tissues. In normal bronchial epithelium, ezrin was mainly localized on the apical membrane, while in lung cancers and metastatic foci, ezrin was primarily distributed in cytoplasm. Among lung cancer tissues, expression of ezrin was higher in the invasive front of primary lesions and the highest in lymphatic metastasis. Statistical analysis demonstrated that ezrin expression correlated significantly with lymphatic metastasis and advanced TNM stage. Our data suggest that ezrin may play a crucial role in governing the biological behavior of lung cancer.

56 citations

Journal ArticleDOI
TL;DR: The current understanding of sphingolipid regulation of the cytoskeleton is described, the biologies in which ERM proteins have been involved, and how these two large fields have started to converge are described.

55 citations


Cites background from "Prognostic Implication of Ezrin Ove..."

  • ...In fact, ezrin predicted decreasedmetastasis-free survival [86]....

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  • ...Ezrin overexpression in myxofibrosarcomawas associated with a higher histological grade of pathology and cancer stage [86]....

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Journal ArticleDOI
TL;DR: Based on exome/transcriptome sequencing and DNA methylation analysis, the authors identify driver genes and methylation clusters associated with unique combinations of mutations, outcomes, and immune cell compositions in Myxofibrosarcoma.
Abstract: Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing (N = 41), RNA sequencing (N = 29), and methylation analysis (N = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes including ATRX, JAK1, NF1, NTRK1, and novel oncogenic BRAF fusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS.

47 citations

Journal ArticleDOI
Jianwei Li1, Kuanhai Wei1, Hailang Yu1, Dan Jin1, Gang Wang1, Bin Yu1 
TL;DR: A systematic review and meta-analysis suggests that Ezrin may be a potential prognostic marker in cancer patients because high Ezrin is associated with a poor prognosis in a variety of solid tumors.
Abstract: More and more studies have investigated the effects of Ezrin expression level on the prognostic role in various tumors. However, the results remain controversial rather than conclusive. Here, we performed a systematic review and meta-analysis to evaluate the correlation of Ezrin expression with the prognosis in various tumors. the pooled hazard ratios (HR) with the corresponding 95% confidence intervals (95% CI) were calculated to evaluate the degree of the association. The overall results of fifty-five studies with 6675 patients showed that elevated Ezrin expression was associated with a worse prognosis in patients with cancers, with the pooled HRs of 1.86 (95% CI: 1.51-2.31, P < 0.001) for over survival (OS), 2.55 (95% CI: 2.14-3.05, P < 0.001) for disease-specific survival (DFS) and 2.02 (95% CI: 1.13-3.63, P = 0.018) for disease-specific survival (DSS)/metastasis-free survival (MFS) by the random, fixed and random effect model respectively. Similar results were also observed in the stratified analyses by tumor types, ethnicity background and sample source. This meta-analysis suggests that Ezrin may be a potential prognostic marker in cancer patients. High Ezrin is associated with a poor prognosis in a variety of solid tumors.

45 citations

References
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Journal ArticleDOI
TL;DR: The ezrin–radixin–moesin (ERM) proteins are crucial components that provide a regulated linkage between membrane proteins and the cortical cytoskeleton, and also participate in signal-transduction pathways.
Abstract: A fundamental property of many plasma-membrane proteins is their association with the underlying cytoskeleton to determine cell shape, and to participate in adhesion, motility and other plasma-membrane processes, including endocytosis and exocytosis. The ezrin–radixin–moesin (ERM) proteins are crucial components that provide a regulated linkage between membrane proteins and the cortical cytoskeleton, and also participate in signal-transduction pathways. The closely related tumour suppressor merlin shares many properties with ERM proteins, yet also provides a distinct and essential function.

1,347 citations


"Prognostic Implication of Ezrin Ove..." refers background in this paper

  • ...As a member of the ezrin-radixin-moesin (ERM) protein family, ezrin functions as a linker between the plasma membrane and cortical actin cytoskeleton.(4) Similar to other Society of Surgical Oncology 2010...

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  • ...However, to modulate cytoskeletal rearrangements, the Thr(567) residue at the C-terminal domain of ezrin must be activated by phosphorylation to convert ezrin from a dormant cytoplasmic form to a membrane- and actin-binding conformation.(4) Accordingly, we further compared the endogenous expression and activation status of ezrin protein in myxofibrosarcoma cell lines versus KELFIB fibroblasts....

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  • ...Ezrin functions to integrate various oncogenic signals for cytoskeletal rearrangements via interaction with multiple classes of transmembrane receptors, including CD44, intergrins, and various receptor tyrosine kinases.(4,6,11,22) Among the last, epidermal growth factor receptor and cMet are known to induce the N-terminal tyrosine phosphorylation of ezrin to promote cytoskeletal reorganization and consequent morphogenetic alterations....

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  • ...Through modulation of diverse actin-based functions, ezrin is known as a key component of the molecular chain connecting metastasis-associated cell surface proteins to the signal transduction network.(4,6,21) Despite variation in intensity, phospho-ezrin at Thr(567), the hallmark of ezrin activation, was only detected in myxofibrosarcoma cell 0....

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Journal ArticleDOI
TL;DR: The FNCLCC system showed slightly increased ability to predict distant metastasis development and tumor mortality, and the use of this system to evaluate STS aggressiveness might be favored.
Abstract: PURPOSESeveral histologic grading systems have been validated in soft tissue sarcomas (STS), but no system is currently accepted worldwide. The National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems were examined comparatively in the same population of patients with STS to determine which system is the best prognosticator with regard to metastasis development and tumor mortality.PATIENTS AND METHODSFour hundred ten adult patients with nonmetastatic STS were examined. Histologic grade was established according to the NCI and FNCLCC systems in each case. The prognostic value of both systems was examined using univariate and multivariate (Cox's model) analyses, and special attention was devoted to tumors with discordant grades.RESULTSIn univariate analysis, both the NCI and FNCLCC systems were of prognostic value to predict metastasis development and tumor mortality. In multivariate analysis, high-grade tumors, irrespective of the system used, size > or = 10 cm...

734 citations


"Prognostic Implication of Ezrin Ove..." refers methods in this paper

  • ...Histological grading and staging were classified according to the updated French Federation of Cancer Centers (FNCLCC) scheme and the American Joint Committee on Cancer (AJCC) system, 6th edition, respectively.(14,15) Retrospective clinical data collection and tissue procurement were in accordance with the local guidelines of research ethics (IRB 99-0506B and 099-04-005)....

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Journal ArticleDOI
TL;DR: A significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients is found and Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT.
Abstract: Metastatic cancers, once established, are the primary cause of mortality associated with cancer. Previously, we used a genomic approach to identify metastasis-associated genes in cancer. From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane. In a mouse model of osteosarcoma, a highly metastatic pediatric cancer, we found ezrin to be necessary for metastasis. By imaging metastatic cells in the lungs of mice, we showed that ezrin expression provided an early survival advantage for cancer cells that reached the lung. AKT and MAPK phosphorylation and activity were reduced when ezrin protein was suppressed. Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT. To define the relevance of ezrin in the biology of metastasis, beyond the founding mouse model, we examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.

689 citations


"Prognostic Implication of Ezrin Ove..." refers background in this paper

  • ...Among the latter, ezrin overexpression has been recently shown to promote dissemination of pediatric rhabdomyosarcomas and osteosarcomas.(9,10) Its underlying mechanistic basis may be ascribed to increased activated ezrin-implicating signaling programs to modulate pleiotropic cellular phenotypes related to cancerous states, such as substrate adhesion, cell survival, cell migration, and formation of cell–cell junctions....

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  • ...Although the requirement for ezrin in cancer cells to enable successful metastasis seems clear, the regulatory mechanism underlying its overexpression remains less understood.(6,9,10) In rhabdomyosarcomas, ezrin was suggested to be a downstream target of Six-1 homeobox gene, which transcriptionally upregulates ezrin expression to promote metastatic progression....

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Journal ArticleDOI
TL;DR: In vivo functional studies revealed that the actin filament–plasma membrane linker ezrin and the homeodomain-containing transcription factor Six-1 had essential roles in determining the metastatic fate of RMS cells.
Abstract: Patients presenting with metastatic rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, have a very poor clinical prognosis. This is due, in large part, to our rudimentary knowledge of the molecular events that dictate metastatic potential. We used cDNA microarray analysis of RMS cell lines, derived from Ink4a/Arf-deficient mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF), to identify a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies revealed that the actin filament-plasma membrane linker ezrin (encoded by Vil2) and the homeodomain-containing transcription factor Six-1 (sine oculis-related homeobox-1 homolog) had essential roles in determining the metastatic fate of RMS cells. VIL2 and SIX1 expression was enhanced in human RMS tissue, significantly correlating with clinical stage. The identification of ezrin and Six-1 as critical regulators of metastasis in RMS provides new mechanistic and therapeutic insights into this pediatric cancer.

511 citations


"Prognostic Implication of Ezrin Ove..." refers background or result in this paper

  • ...Among the last, epidermal growth factor receptor and cMet are known to induce the N-terminal tyrosine phosphorylation of ezrin to promote cytoskeletal reorganization and consequent morphogenetic alterations.(10,23) To date, there is a lack of data on the upstream mechanisms of ezrin activation in myxofibrosarcomas, while our unpublished observation indicated that c-Met protein overexpression, accompanied by mRNA upregulation, is a frequent event in this sarcoma entity....

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  • ...Among the latter, ezrin overexpression has been recently shown to promote dissemination of pediatric rhabdomyosarcomas and osteosarcomas.(9,10) Its underlying mechanistic basis may be ascribed to increased activated ezrin-implicating signaling programs to modulate pleiotropic cellular phenotypes related to cancerous states, such as substrate adhesion, cell survival, cell migration, and formation of cell–cell junctions....

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  • ...In rhabdomyosarcomas, ezrin was suggested to be a downstream target of Six-1 homeobox gene, which transcriptionally upregulates ezrin expression to promote metastatic progression.(10) This was in keeping with our results of real-time PCR quantification and Western blot testing, showing concordance in expression levels of total ezrin between mRNA and protein....

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  • ...Although the requirement for ezrin in cancer cells to enable successful metastasis seems clear, the regulatory mechanism underlying its overexpression remains less understood.(6,9,10) In rhabdomyosarcomas, ezrin was suggested to be a downstream target of Six-1 homeobox gene, which transcriptionally upregulates ezrin expression to promote metastatic progression....

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