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Taqi M, ul Rasool H, Zaka Haider M, Al Muderis M. Significance of Biogenetic Markers in Giant Cell Tumor Differentiation and Prognosis: A Narrative Review. Diagnostics (Basel) 2024; 15:39. [PMID: 39795567 PMCID: PMC11719472 DOI: 10.3390/diagnostics15010039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/27/2024] [Accepted: 11/30/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Giant cell tumor of bone (GCTB) is a locally aggressive tumor. It accounts for only 5% of all bony tumors. Early diagnosis, and follow-up for recurrence is often difficult due to a lack of biogenetic markers. Giant cells are multinucleated epithelioid cells derived from macrophages. Histologically, giant cells are also present in other pathologies of bone, e.g., aneurysmal bone cyst, chondroblastoma, giant cell granuloma, and malignant giant cell tumor, etc. Similarly, radiographic findings overlap with other osteolytic lesions, making the diagnosis and prognosis of giant cell tumor very challenging. Aims and Objectives: The purpose of this study was to explore biological and genetic markers which can be used for detection, differentiation, recurrence, and prognosis of GCTB. This will help to better understand the clinical outcome of GCTB and minimize the need for interventions. Methods: We conducted a literature search using Google, Google Scholar, PubMed, Wiley Library, Medline, Clinical trials.org, and Web of Science. Our search strategy included MeSH terms and key words for giant cell tumor and biogenetic markers from date of inception to September 2020. After excluding review articles, 246 duplicates, and non-relevant articles, we included 24 articles out of 1568 articles, summarizing the role of biogenetic markers in the prognosis of GCT. Results: P63 is 98.6% sensitive and relatively specific for GCT as compared to other multinucleated giant cells containing neoplasms. MDM2 (mouse double minute 2 homolog), IGF1 (insulin-like growth factor 1), STAT1 (signal transducer and activator of transcription 1), and RAC1 (Ras-related C3 botulinum toxin substrate 1) are associated with GCTB recurrence, and might serve as biomarkers for it. Increased expression of the proteins STAT5B, GRB2, and OXSR1 was related to a higher probability of metastasis. H3F3A and H3F3B mutation analysis appears to be a highly specific, although less sensitive, diagnostic tool for the distinction of giant cell tumor of bone (GCTB) and chondroblastoma from other giant cell-containing tumors. A neutrophil to lymphocyte ratio (NLR) > 2.70, platelet to lymphocyte ratio (PLR) > 215.80, lymphocyte to monocyte ratio (LMR) ≤ 2.80, and albumin to globulin ratio (AGR) < 1.50 were significantly associated with decreased disease-free survival (DFS) (p < 0.05). Large amounts of osteoclast-related mRNA (cathepsin K, tartrate-resistant acid phosphatase, and matrix metalloproteinase9) in GCTs (p < 0.05) are associated with the grade of bone resorption. We propose that subarticular primary malignant bone sarcomas with H3.3 mutations represent true malignant GCTB, even in the absence of a benign GCTB component. IMP3 and IGF2 might be potential biomarkers for GCT of the spine in regulating the angiogenesis of giant cell tumor of bone and predicting patients' prognosis. Conclusions: This review study shows serological markers, genetic factors, cell membrane receptor markers, predictive markers for malignancy, and prognostic protein markers which are highly sensitive for GCT and relatively specific for giant cell tumor. MDM2, IGF1, STAT1, RAC1 are important makers in determining recurrence, while P63 and H3F3A differentiate GCT from other giant cell-containing tumors. STAT5B, GRB2, and OXSR1 are significant in determining the prognosis of GCT. Apart from using radiological and histological parameters, we can add them to tumor work-up for definitive diagnosis and prognosis.
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Affiliation(s)
- Muhammad Taqi
- Orthopedic Surgery, Macquarie University Hospital, Sydney, NSW 2113, Australia
| | - Haseeb ul Rasool
- Internal Medicine Department, Icahn School of Medicine Mount Sinai, New York, NY 10029, USA
| | - Mobeen Zaka Haider
- Internal Medicine Department, Carle Foundation Hospital, Urbana, IL 61801, USA
| | - Munjed Al Muderis
- Orthopedic Surgery, Macquarie University Hospital, Sydney, NSW 2113, Australia
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Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints. Cancers (Basel) 2022; 14:cancers14225633. [PMID: 36428727 PMCID: PMC9688455 DOI: 10.3390/cancers14225633] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/04/2022] [Accepted: 11/13/2022] [Indexed: 11/19/2022] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cancer cells, which can both enhance sensitivity to Immune Checkpoint Inhibitors (ICIs). Despite the recent approval of ICIs for a number of advanced cancer types based on their ability to reinvigorate T-cell-mediated antitumor immune responses, a consistent percentage of treated patients fail to respond, strongly encouraging the identification of combination therapies to overcome resistance. In the present review, we analyzed both established and unexplored mechanisms that may be elicited by PARPi, supporting immune reactivation and their potential synergism with currently used ICIs. This analysis may indicate novel and possibly patient-specific immune features that might represent new pharmacological targets of PARPi, potentially leading to the identification of predictive biomarkers of response to their combination with ICIs.
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Barik GK, Sahay O, Paul D, Santra MK. Ezrin gone rogue in cancer progression and metastasis: An enticing therapeutic target. Biochim Biophys Acta Rev Cancer 2022; 1877:188753. [PMID: 35752404 DOI: 10.1016/j.bbcan.2022.188753] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/16/2022] [Accepted: 06/18/2022] [Indexed: 12/12/2022]
Abstract
Cancer metastasis is the primary cause of morbidity and mortality in cancer as it remains the most complicated, devastating, and enigmatic aspect of cancer. Several decades of extensive research have identified several key players closely associated with metastasis. Among these players, cytoskeletal linker Ezrin (the founding member of the ERM (Ezrin-Radixin-Moesin) family) was identified as a critical promoter of metastasis in pediatric cancers in the early 21st century. Ezrin was discovered 40 years ago as a aminor component of intestinal epithelial microvillus core protein, which is enriched in actin-containing cell surface structures. It controls gastric acid secretion and plays diverse physiological roles including maintaining cell polarity, regulating cell adhesion, cell motility and morphogenesis. Extensive research for more than two decades evinces that Ezrin is frequently dysregulated in several human cancers. Overexpression, altered subcellular localization and/or aberrant activation of Ezrin are closely associated with higher metastatic incidence and patient mortality, thereby justifying Ezrin as a valuable prognostic biomarker in cancer. Ezrin plays multifaceted role in multiple aspects of cancer, with its significant contribution in the complex metastatic cascade, through reorganizing the cytoskeleton and deregulating various cellular signaling pathways. Current preclinical studies using genetic and/or pharmacological approaches reveal that inactivation of Ezrin results in significant inhibition of Ezrin-mediated tumor growth and metastasis as well as increase in the sensitivity of cancer cells to various chemotherapeutic drugs. In this review, we discuss the recent advances illuminating the molecular mechanisms responsible for Ezrin dysregulation in cancer and its pleiotropic role in cancer progression and metastasis. We also highlight its potential as a prognostic biomarker and therapeutic target in various cancers. More importantly, we put forward some potential questions, which we strongly believe, will stimulate both basic and translational research to better understand Ezrin-mediated malignancy, ultimately leading to the development of Ezrin-targeted cancer therapy for the betterment of human life.
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Affiliation(s)
- Ganesh Kumar Barik
- Cancer Biology Division, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India; Department of Biotechnology, Savitribai Phule Pune University, Ganeshkhind Road, Pune, Maharashtra 411007, India
| | - Osheen Sahay
- Cancer Biology Division, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India; Department of Biotechnology, Savitribai Phule Pune University, Ganeshkhind Road, Pune, Maharashtra 411007, India
| | - Debasish Paul
- Laboratory of Cancer Biology and Genetics, Centre for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Manas Kumar Santra
- Cancer Biology Division, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India.
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Abstract
Simple Summary Cell migration is an essential process from embryogenesis to cell death. This is tightly regulated by numerous proteins that help in proper functioning of the cell. In diseases like cancer, this process is deregulated and helps in the dissemination of tumor cells from the primary site to secondary sites initiating the process of metastasis. For metastasis to be efficient, cytoskeletal components like actin, myosin, and intermediate filaments and their associated proteins should co-ordinate in an orderly fashion leading to the formation of many cellular protrusions-like lamellipodia and filopodia and invadopodia. Knowledge of this process is the key to control metastasis of cancer cells that leads to death in 90% of the patients. The focus of this review is giving an overall understanding of these process, concentrating on the changes in protein association and regulation and how the tumor cells use it to their advantage. Since the expression of cytoskeletal proteins can be directly related to the degree of malignancy, knowledge about these proteins will provide powerful tools to improve both cancer prognosis and treatment. Abstract Successful metastasis depends on cell invasion, migration, host immune escape, extravasation, and angiogenesis. The process of cell invasion and migration relies on the dynamic changes taking place in the cytoskeletal components; actin, tubulin and intermediate filaments. This is possible due to the plasticity of the cytoskeleton and coordinated action of all the three, is crucial for the process of metastasis from the primary site. Changes in cellular architecture by internal clues will affect the cell functions leading to the formation of different protrusions like lamellipodia, filopodia, and invadopodia that help in cell migration eventually leading to metastasis, which is life threatening than the formation of neoplasms. Understanding the signaling mechanisms involved, will give a better insight of the changes during metastasis, which will eventually help targeting proteins for treatment resulting in reduced mortality and longer survival.
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Ferrari MVO, da Costa WH, Matushita MAM, Meduna RR, Brazao ES, Bezerra SM, da Cunha IW, Zequi SDC. Immunohistochemical negative expression of ezrin predicts poor prognosis in clear cell renal cell carcinoma. Urol Oncol 2019; 38:75.e1-75.e7. [PMID: 31648868 DOI: 10.1016/j.urolonc.2019.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/12/2019] [Accepted: 09/19/2019] [Indexed: 12/24/2022]
Abstract
PURPOSE To analyze the immunohistochemical expression of ezrin and moesin in clear cell renal cell carcinoma (ccRCC). These proteins, as part of the ezrin-radixin-moesin complex link the cell membrane to the actin cytoskeleton, affecting such processes as cell adhesion, cell survival, cell motility, and signal transduction. Our aim was to examine the impact of their expression on clinical outcomes and survival rates. PATIENTS AND METHODS Five hundred seventy-five consecutive patients who had been treated surgically for ccRCC in a single center between 1985 and 2016 were selected. A single pathologist reviewed all cases to perform a uniform reclassification and determined the most representative tumor areas for construction of a tissue microarray. RESULTS Of all ccRCC specimens, 106 (18.3%) were negative for ezrin, and 469 (81.7%) had positive ezrin expression; 16 (2.8%) were negative and 559 (97.2%) were positive for moesin, respectively. Ezrin expression was associated with pT stage (P < 0.001), clinical stage (P = 0.012), synchronic metastasis (P < 0.001), incidental tumors (P = 0.007), and International Society of Urological Pathology histological grade (P = 0.025). There was a correlation between moesin expression and clinical stage (P = 0.027), pT stage (P = 0.025), and pN stage (P = 0.007). Ezrin expression significantly influenced tumor-related deaths. By multivariate analysis, negative ezrin expression was an independent risk factor for disease-specific survival (HR 1.89; 95% CI 1.11-3.20). CONCLUSIONS Negativity for ezrin in ccRCC patients significantly impacts survival rates. We encourage further prospective studies to analyze ezrin analysis to evaluate its significance in the prognosis of ccRCC.
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Affiliation(s)
| | | | | | | | | | | | | | - Stenio de Cassio Zequi
- Urology Division, A.C. Camargo Cancer Center, São Paulo, Brazil; Researches of INCiTO-INOTE Institute, Brazil
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Qiu C, Huang F, Zhang Q, Chen W, Zhang H. miR-205-3p promotes proliferation and reduces apoptosis of breast cancer MCF-7 cells and is associated with poor prognosis of breast cancer patients. J Clin Lab Anal 2019; 33:e22966. [PMID: 31578772 PMCID: PMC6805278 DOI: 10.1002/jcla.22966] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/03/2019] [Accepted: 06/05/2019] [Indexed: 12/24/2022] Open
Abstract
Background To study the expression of microribonucleic acid (miR)‐205 in breast cancer and its effects on the proliferation and apoptosis of breast cancer cells. Methods Breast cancer cell line MCF‐7 cells with stable expression of miR‐205‐3p were constructed. Cell proliferation, invasion, and apoptosis were detected via MTT assay, transwell assay, and flow cytometry, respectively. The expressions of Ezrin, LaminA/C, cleaved caspase‐3, Bcl‐2, and Bax were detected via Western blotting. The expressions of miR‐205‐3p in breast cancer tissues and para‐carcinoma tissues were detected via quantitative PCR (qPCR). Results In transfection group, cell proliferation and invasion capacities were increased significantly (P < 0.01), but apoptotic cells were significantly reduced (P < 0.01). In addition, the expressions of Ezrin, LaminA/C, and cleaved caspase‐3 in the transfection group were significantly decreased (P < 0.01), but the Bcl‐2/Bax ratio was significantly increased (P < 0.01). The miR‐205‐3p expression in tumor tissues of breast cancer patients was significantly higher than that in para‐carcinoma tissue, but Ezrin, LaminA/C, and cleaved caspase‐3 expressions in tumor tissues were remarkably declined (P < 0.01), while the Bcl‐2/Bax ratio was remarkably increased (P < 0.01). Moreover, the 5‐year survival of patients with high expression of miR‐205‐3p was significantly shorter than patients with normal or low expression (P < 0.01). Conclusion Highly expressed miR‐205‐3p can promote the proliferation and invasion and reduce the apoptosis of breast cancer cells, and the high expression of miR‐205‐3p can significantly reduce the survival time of patients.
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Affiliation(s)
- Changhong Qiu
- Department of General Surgery, The First People's Hospital of ZhaoQing, ZhaoQing, China
| | - Fei Huang
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-Sen University (Shen Zhen), Shen Zhen, China
| | - Qing Zhang
- Department of General Surgery, The First People's Hospital of ZhaoQing, ZhaoQing, China
| | - Wei Chen
- Department of General Surgery, The First People's Hospital of ZhaoQing, ZhaoQing, China
| | - Huiting Zhang
- Department of General Surgery, The First People's Hospital of ZhaoQing, ZhaoQing, China
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Mohanraj R, Ramani P, Premkumar P, Natesan A, Sherlin HJ, Sukumaran G. Immunohistochemical Expression Of Ezrin In Oral Potentially Malignant Disorders-A Descriptive Study. J Pharm Bioallied Sci 2017; 9:S205-S210. [PMID: 29284965 PMCID: PMC5731014 DOI: 10.4103/jpbs.jpbs_139_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Introduction: Ezrin, also known as cytovillin, is a member of the ERM family of protein. Ezrin cross-links actin filament with the plasma membrane. They are involved in the formation of microvilli, cell–cell adhesion, maintenance of cell shape, cell motility, and membrane trafficking. Recent analysis reveals their involvement in signaling pathways. Ezrin is highly expressed in several types of human cancers, and correlation between its immunoreactivity and histopathological data as well as the patient outcome has previously been studied. Objective: The objective of the study was to analyze the immunohistochemical expression pattern of ezrin in oral potentially malignant disorders (OPMDs), namely, oral submucous fibrosis (OSMF) with different grades and clinically leucoplakia (hyperkeratosis with various degree of dysplasia) and its use as a predictive marker for malignant transformation. Subjects and Methods: Sample size n = 43, histopathologically confirmed cases of OPMDs (13 cases of OSMF with different grades and 30 cases of clinically leukoplakia) were retrieved from the Department of Oral and Maxillofacial Pathology. Immunohistochemistry was done using anti-ezrin antibody, and the expression was graded in terms of proportion and intensity. Results: There was a significant expression of ezrin in OPMDs, and its cytoplasmic shift can be used as a predictive marker for malignant transformation. Conclusion: The findings of the current study revealed that the expression of ezrin in OPMDs may be related to the progression of the disease.
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Affiliation(s)
- Raghini Mohanraj
- Department of Oral Pathology and Microbiology, Madha Dental College and Hospital, Chennai, Tamil Nadu, India
| | - Pratibha Ramani
- Department of Oral Pathology and Microbiology, Saveetha Dental College, Saveetha University, Chennai, Tamil Nadu, India
| | - Priya Premkumar
- Department of Oral Pathology and Microbiology, Saveetha Dental College, Saveetha University, Chennai, Tamil Nadu, India
| | - Anuja Natesan
- Department of Oral Pathology and Microbiology, Saveetha Dental College, Saveetha University, Chennai, Tamil Nadu, India
| | - Herald J Sherlin
- Department of Oral Pathology and Microbiology, Saveetha Dental College, Saveetha University, Chennai, Tamil Nadu, India
| | - Gheena Sukumaran
- Department of Oral Pathology and Microbiology, Saveetha Dental College, Saveetha University, Chennai, Tamil Nadu, India
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Demacopulo B, Lema BE, Cabrini RL, Kreimann EL. Similar expression pattern of NHERF1 and EZRIN in papillary but not in solid areas of human serous ovarian carcinomas. Acta Histochem 2016; 118:797-805. [PMID: 27823775 DOI: 10.1016/j.acthis.2016.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 10/19/2016] [Accepted: 10/24/2016] [Indexed: 01/16/2023]
Abstract
NHERF1 is an adaptor protein expressed in the apical membrane of polarized epithelia, which interacts with the EZRIN-Radixin-Moesin (ERM) family of proteins connecting signaling pathways to the cell cytoskeleton. NHERF1 and EZRIN cooperate in the maintenance of the apical microvilli in polarized epithelial cells. In several types of cancers, NHERF1 and EZRIN are displaced from the apical compartment to the cytoplasm and nuclei of cancer cells. At the present, the distribution of NHERF1 in ovarian tumors is not well known. In this study, NHERF1 expression was examined by immunohistochemistry in cyst adenofibromas, serous borderline tumors, and serous ovarian carcinomas. We observed a strong staining of NHERF1 and EZRIN at the membrane level of borderline tumors and areas of papillary structures in ovarian carcinomas. In tumors without papillary structures and compact structure, NHERF1 was exclusively expressed in the apical pole of the cells at the edges of the clefts of luminal spaces. In contrast, positive expression of EZRIN was found in the membrane of tumor cells within the solid tumor where NHERF1 was not expressed. In summary, this study shows, for the first time, the distribution of NHERF1 in ovarian cancer and reveals a different regulation of NHERF1 and EZRIN expression in ovarian tumors which represents the complexity of the molecular changes of this disease.
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Affiliation(s)
- Brenda Demacopulo
- National Atomic Energy Commission of Argentina (CNEA), National Research Council of Argentina (CONICET), Department of Radiobiology, Av. General Paz 1499 (1650), San Martín, Buenos Aires, Argentina.
| | - Baltazar Eduardo Lema
- Private Diagnostic Pathology Laboratory, Anchorena 1510 Capital Federal (1425) C.A.B.A., Buenos Aires, Argentina.
| | - Rómulo Luis Cabrini
- National Atomic Energy Commission of Argentina (CNEA), National Research Council of Argentina (CONICET), Department of Radiobiology, Av. General Paz 1499 (1650), San Martín, Buenos Aires, Argentina; School of Dentistry, University of Buenos Aires (UBA), Department of Oral Pathology, Marcelo T. de Alvear 2142, (C1122AAH) C.A.B.A., Buenos Aires, Argentina.
| | - Erica Lorena Kreimann
- National Atomic Energy Commission of Argentina (CNEA), National Research Council of Argentina (CONICET), Department of Radiobiology, Av. General Paz 1499 (1650), San Martín, Buenos Aires, Argentina.
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Ezrin Is Associated with Disease Progression in Ovarian Carcinoma. PLoS One 2016; 11:e0162502. [PMID: 27622508 PMCID: PMC5021292 DOI: 10.1371/journal.pone.0162502] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 08/23/2016] [Indexed: 12/24/2022] Open
Abstract
Objective Ezrin and p130Cas are structural proteins with an important role in signaling pathways and have been shown to promote cancer dissemination. We previously reported on overexpression of both ezrin and p130Cas in breast carcinoma effusions compared to primary carcinomas. Since ovarian and breast carcinomas share the ability to disseminate by forming malignant effusions, we sought to study the role of these molecules in ovarian carcinoma (OC). Methods OC cell lines were cultured in two different 3-dimensional conditions, on alginate scaffolds and as spheroids, which served as models for solid tumor and malignant effusions, respectively. shRNA was used to reduce protein expression in the cells. The malignant potential was evaluated by chemo-invasion assay, branching capacity on Matrigel and rate of proliferation. Subsequently, clinical specimens of high-grade serous carcinoma effusions, ovarian tumors and solid metastases were analyzed for ezrin and p130Cas expression. Results Higher ezrin expression was found in cells composing the spheroids compared to their counterparts cultured on alginate scaffold and in clinical samples of malignant effusions compared to solid tumors. In addition, reduced Ezrin expression impaired the invasion ability and the branching capacity of OC cells to a greater extent than reduced p130Cas expression. However, ezrin and p130Cas expression in effusions was unrelated to clinical outcome. Conclusions The 3-dimensional cell cultures were found to mimic the different tumor sites and be applicable as a model. The in vitro results concur with the clinical specimen analysis, suggesting that in OC, the role of ezrin in disease progression is more pronounced than that of p130Cas.
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Abdou AG, Sakr S, Elwahed MMA, Eladly EK. Immunohistochemical assessment of ezrin and moesin in colorectal carcinoma. Ultrastruct Pathol 2016; 40:181-8. [DOI: 10.3109/01913123.2016.1155683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Guedj N, Vaquero J, Clapéron A, Mergey M, Chrétien Y, Paradis V, Fouassier L. Loss of ezrin in human intrahepatic cholangiocarcinoma is associated with ectopic expression of E-cadherin. Histopathology 2016; 69:211-21. [PMID: 26791814 DOI: 10.1111/his.12931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 01/14/2016] [Indexed: 01/03/2023]
Abstract
AIMS Ezrin connects proteins from the plasma membrane to the subcortical cytoskeleton, and contributes to epithelial integrity by interacting with the cell-cell adhesion molecule E-cadherin. In the liver, ezrin is restricted to cholangiocytes, where it regulates biliary secretory functions. During carcinogenesis, ezrin expression is impaired and associated with enhancement of cell migratory activity in cancer cells; therefore, we aimed to analyse ezrin in cholangiocarcinogenesis. METHODS AND RESULTS Ezrin expression was evaluated by immunohistochemistry on tissue microarrays from 94 surgical specimens of intrahepatic cholangiocarcinoma (CCA), and correlated with clinicopathological factors and E-cadherin expression. Ezrin function was also analysed in human CCA cell lines. In CCA, ezrin was negative/weakly expressed in 49 cases (52%) and moderately/strongly expressed in 45 cases (48%), mostly in cell cytoplasm. The negative/weak expression of ezrin was more frequent in peripheral than in perihilar CCA (P = 0.002), and was associated with high tumour size (P = 0.001), low mucus secretion (P = 0.042), the presence of satellite nodules (P = 0.024), and ectopic cytoplasmic expression of E-cadherin (P = 0.005). In vitro, silencing of ezrin in CCA cells caused internalization of E-cadherin and favoured cell migration. CONCLUSIONS Ezrin is down-regulated during cholangiocarcinogenesis, and its loss results in a more aggressive phenotype.
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Affiliation(s)
- Nathalie Guedj
- Service d'anatomie pathologique Hôpital Beaujon, Clichy, France.,INSERM, UMR 1149, Centre de Recherche sur l'Inflammation, Paris, France
| | - Javier Vaquero
- INSERM, UMR_S 938, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Audrey Clapéron
- INSERM, UMR_S 938, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Martine Mergey
- INSERM, UMR_S 938, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Yves Chrétien
- INSERM, UMR_S 938, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Valérie Paradis
- Service d'anatomie pathologique Hôpital Beaujon, Clichy, France.,INSERM, UMR 1149, Centre de Recherche sur l'Inflammation, Paris, France
| | - Laura Fouassier
- INSERM, UMR_S 938, Paris, France.,Sorbonne Universités, UPMC Université Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
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Prognostic Value of Ezrin in Various Cancers: A Systematic Review and Updated Meta-analysis. Sci Rep 2015; 5:17903. [PMID: 26632332 PMCID: PMC4668575 DOI: 10.1038/srep17903] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 11/09/2015] [Indexed: 12/26/2022] Open
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.
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Syed N, Chavan S, Sahasrabuddhe NA, Renuse S, Sathe G, Nanjappa V, Radhakrishnan A, Raja R, Pinto SM, Srinivasan A, Prasad TSK, Srikumar K, Gowda H, Santosh V, Sidransky D, Califano JA, Pandey A, Chatterjee A. Silencing of high-mobility group box 2 (HMGB2) modulates cisplatin and 5-fluorouracil sensitivity in head and neck squamous cell carcinoma. Proteomics 2015; 15:383-93. [PMID: 25327479 DOI: 10.1002/pmic.201400338] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 09/24/2014] [Accepted: 10/13/2014] [Indexed: 12/16/2022]
Abstract
Dysregulation of protein expression is associated with most diseases including cancer. MS-based proteomic analysis is widely employed as a tool to study protein dysregulation in cancers. Proteins that are differentially expressed in head and neck squamous cell carcinoma (HNSCC) cell lines compared to the normal oral cell line could serve as biomarkers for patient stratification. To understand the proteomic complexity in HNSCC, we carried out iTRAQ-based MS analysis on a panel of HNSCC cell lines in addition to a normal oral keratinocyte cell line. LC-MS/MS analysis of total proteome of the HNSCC cell lines led to the identification of 3263 proteins, of which 185 proteins were overexpressed and 190 proteins were downregulated more than twofold in at least two of the three HNSCC cell lines studied. Among the overexpressed proteins, 23 proteins were related to DNA replication and repair. These included high-mobility group box 2 (HMGB2) protein, which was overexpressed in all three HNSCC lines studied. Overexpression of HMGB2 has been reported in various cancers, yet its role in HNSCC remains unclear. Immunohistochemical labeling of HMGB2 in a panel of HNSCC tumors using tissue microarrays revealed overexpression in 77% (54 of 70) of tumors. The HMGB proteins are known to bind to DNA structure resulting from cisplatin-DNA adducts and affect the chemosensitivity of cells. We observed that siRNA-mediated silencing of HMGB2 increased the sensitivity of the HNSCC cell lines to cisplatin and 5-FU. We hypothesize that targeting HMGB2 could enhance the efficacy of existing chemotherapeutic regimens for treatment of HNSCC. All MS data have been deposited in the ProteomeXchange with identifier PXD000737 (http://proteomecentral.proteomexchange.org/dataset/PXD000737).
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Affiliation(s)
- Nazia Syed
- Institute of Bioinformatics, International Technology Park, Bangalore, India; Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
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Zhang J, Dong J, Yang Z, Ma X, Zhang J, Li M, Chen Y, Ding Y, Li K, Zhang Z. Expression of ezrin, CD44, and VEGF in giant cell tumor of bone and its significance. World J Surg Oncol 2015; 13:168. [PMID: 25929323 PMCID: PMC4434870 DOI: 10.1186/s12957-015-0579-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 04/08/2015] [Indexed: 11/23/2022] Open
Abstract
Background This research aimed to study the role of ezrin, CD44, and VEGF in invasion, metastasis, recurrence, and prognosis of giant cell tumor of bone (GCTB) and its association with the clinical and pathological features of GCTB. Methods Expression status of ezrin, CD44, and VEGF in 80 GCTB tissues and its adjacent noncancerous tissue samples were measured with immunohistochemical and Elivison staining. Their correlation with the clinical and pathologic factors was statistically analyzed by chi-square test. Results The expression status of ezrin, CD44, and VEGF were significantly higher in GCTB tissue samples than in its adjacent noncancerous tissue samples and in GCTB at Campanacci stage III than in Campanacci stages I and II (P < 0.05). No significant difference was found in age and sex of the patients and locations of the tumor (P > 0.05). Survival analysis showed that the expression status of ezrin, CD44, VEGF, and Campanacci clinical stages of GCTB were positively associated with the survival rate of GCTB patients and negatively associated with ezrin and Campanacci stages of GCTB, indicating that ezrin, CD44, VEGF, and Campanacci clinical stages of GCTB are the independent factors for GCTB. Conclusions Ezrin, CD44, and VEGF are over-expressed in GCTB tissue and its adjacent noncancerous tissue samples and may play an important role in the occurrence, invasion, metastasis, and recurrence of GCTB. Measurement of ezrin, CD44, and VEGF expression status may contribute to the judgment of prognosis of GCTB patients.
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Affiliation(s)
- Jing Zhang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, People's Republic of China.
| | - Jian Dong
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, People's Republic of China.
| | - Zuozhang Yang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, People's Republic of China.
| | - Xiang Ma
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, People's Republic of China.
| | - Jinlei Zhang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, People's Republic of China.
| | - Mei Li
- Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, People's Republic of China.
| | - Yun Chen
- Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, People's Republic of China.
| | - Yingying Ding
- Department of Radiology, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, People's Republic China.
| | - Kun Li
- Department of Radiology, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, People's Republic China.
| | - Zhiping Zhang
- Department of Radiology, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, People's Republic China.
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Li J, Li L, Li Z, Gong G, Chen P, Liu H, Wang J, Liu Y, Wu X. The role of miR-205 in the VEGF-mediated promotion of human ovarian cancer cell invasion. Gynecol Oncol 2015; 137:125-33. [PMID: 25597268 DOI: 10.1016/j.ygyno.2015.01.531] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 01/07/2015] [Accepted: 01/12/2015] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Our objective was to investigate a miRNA pathway that acts downstream of VEGF-induced invasion of ovarian cancer cells. METHOD We used two paired high and low metastatic serous ovarian cancer cells to demonstrate the role of miR-205 in VEGF-induced invasion of ovarian cancer cells and to investigate the gene targets of miR-205. RESULTS Our previous comparative proteomics studies showed that VEGF decreased the expression of Ezrin and Lamin A/C, and this result was validated in the present study using qPCR and Western blotting. Then we found that VEGF enhanced the invasiveness of and inhibited apoptosis in ovarian cancer cells as assessed by transwell invasion assays and Annexin V-FITC immunostaining, respectively. VEGFR was also expressed in ovarian cancer cells, as assessed by immunocytochemical staining. Furthermore, using the dual-luciferase report assay system, we demonstrated that miR-205 targeted Ezrin and Lamin A/C. MiR-205 was up-regulated in ovarian cancer cells exposed to VEGF, as determined by miRNA microarray analysis and verified by qPCR. MiR-205 promoted the invasion and proliferation of ovarian cancer cells. CONCLUSION Our data reveal a new potential pathway in which VEGF promotes the invasion of ovarian cancer cells, partially via the down-regulation of Ezrin and Lamin A/C caused by increased expression of miR-205.
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Affiliation(s)
- Juanni Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Long Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Zexia Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Microarray Core Facility, University of Texas Southwestern Medical Center, 75070, USA
| | - Guanghui Gong
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Puxiang Chen
- Department of Gynecology and Obstetrics, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Hailing Liu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Junpu Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Ying Liu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Xiaoying Wu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, China.
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Zhang F, Li C, Liu H, Wang Y, Chen Y, Wu X. The functional proteomics analysis of VEGF-treated human epithelial ovarian cancer cells. Tumour Biol 2014; 35:12379-87. [DOI: 10.1007/s13277-014-2552-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 08/25/2014] [Indexed: 12/12/2022] Open
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Zhang C, Wu Y, Xuan Z, Zhang S, Wang X, Hao Y, Wu J, Zhang S. p38MAPK, Rho/ROCK and PKC pathways are involved in influenza-induced cytoskeletal rearrangement and hyperpermeability in PMVEC via phosphorylating ERM. Virus Res 2014; 192:6-15. [PMID: 25150189 DOI: 10.1016/j.virusres.2014.07.027] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 07/04/2014] [Accepted: 07/28/2014] [Indexed: 12/27/2022]
Abstract
Severe influenza infections are featured by acute lung injury, a syndrome of pulmonary microvascular leak. A growing number of evidences have shown that the pulmonary microvascular endothelial cells (PMVEC) are critical target of influenza virus, promoting microvascular leak. It is reported that there are multiple mechanisms by which influenza virus could elicit increased pulmonary endothelial permeability, in both direct and indirect manners. Ezrin/radixin/moesin family proteins, the linkers between plasma membrane and actin cytoskeleton, have been reported to be involved in cell adhesion, motility and may modulate endothelial permeability. Studies have also shown that ERM is phosphorylated in response to various stimuli via p38MAPK, Rho/ROCK or PKC pathways. However, it is unclear that whether influenza infection could induce ERM phosphorylation and its relocalization. In the present study, we have found that there are cytoskeletal reorganization and permeability increases in the course of influenza virus infection, accompanied by upregulated levels of p-ERM. p-ERM's aggregation along the periphery of PMVEC upon influenza virus infection was detected via confocal microscopy. Furthermore, we sought to determine the role of p38MAPK, Rho/ROCK and PKC pathways in ERM phosphorylation as well as their involvement in influenza virus-induced endothelial malfunction. The activation of p38MAPK, Rho/ROCK and PKC pathways upon influenza virus stimulation were observed, as evidenced by the evaluation of phosphorylated p38 (p-p38), phosphorylated MKK (p-MKK) in p38MAPK pathway, ROCK1 in Rho/ROCK pathway and phosphorylated PKC (p-PKC) in PKC pathway. We also showed that virus-induced ERM phosphorylation was reduced by using p38MAPK inhibitor, SB203580 (20 μM), Rho/ROCK inhibitor, Y27632 (20 μM), PKC inhibitor, LY317615 (10 μM). Additionally, influenza virus-induced F-actin reorganization and hyperpermeability were attenuated by pretreatment with SB203580, Y27632 and LY317615. Taken together, we provide the first evidence that p38MAPK, Rho/ROCK and PKC are involved in influenza-induced cytoskeletal changes and permeability increases in PMVEC via phosphorylating ERM.
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Affiliation(s)
- Chenyue Zhang
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China
| | - Ying Wu
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Zinan Xuan
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China
| | - Shujing Zhang
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China
| | - Xudan Wang
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China
| | - Yu Hao
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China
| | - Jun Wu
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China
| | - Shu Zhang
- Department of Microbiology and Immunology, Beijing University of Chinese Medicine, Beijing, PR China
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CHEN MIAOJUAN, GAO XUEJUAN, XU LINA, LIU TENGFEI, LIU XIAOHUI, LIU LANGXIA. Ezrin is required for epithelial-mesenchymal transition induced by TGF-β1 in A549 cells. Int J Oncol 2014; 45:1515-22. [PMID: 25051016 DOI: 10.3892/ijo.2014.2554] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Accepted: 07/02/2014] [Indexed: 11/05/2022] Open
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Andersson G, Wennersten C, Gaber A, Boman K, Nodin B, Uhlén M, Segersten U, Malmström PU, Jirström K. Reduced expression of ezrin in urothelial bladder cancer signifies more advanced tumours and an impaired survival: validatory study of two independent patient cohorts. BMC Urol 2014; 14:36. [PMID: 24885195 PMCID: PMC4049499 DOI: 10.1186/1471-2490-14-36] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 05/09/2014] [Indexed: 11/11/2022] Open
Abstract
Background Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guérin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104). In the present study, we examined the prognostic significance of ezrin expression in urothelial bladder cancer in a total number of 442 tumours from two independent patient cohorts. Methods Immunohistochemical expression of ezrin was evaluated in tissue microarrays with tumours from one retrospective cohort of bladder cancer (n = 110; cohort I) and one population-based cohort (n = 342; cohort II). Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test and Cox regression proportional hazards’ modeling were used to evaluate the impact of ezrin on 5-year overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS). Results Ezrin expression could be evaluated in tumours from 100 and 342 cases, respectively. In both cohorts, reduced membranous ezrin expression was significantly associated with more advanced T-stage (p < 0.001), high grade tumours (p < 0.001), female sex (p = 0.040 and p = 0.013), and membranous expression of podocalyxin-like protein (p < 0.001 and p = 0.009). Moreover, reduced ezrin expression was associated with a significantly reduced 5-year OS in both cohorts (HR = 3.09 95% CI 1.71-5.58 and HR = 2.15(1.51-3.06), and with DSS in cohort II (HR = 2.77, 95% CI 1.78-4.31). This association also remained significant in adjusted analysis in Cohort I (HR1.99, 95% CI 1.05-3.77) but not in Cohort II. In pTa and pT1 tumours in cohort II, there was no significant association between ezrin expression and time to progression. Conclusions The results from this study validate previous findings of reduced membranous ezrin expression in urothelial bladder cancer being associated with unfavourable clinicopathological characteristics and an impaired survival. The utility of ezrin as a prognostic biomarker in transurethral resection specimens merits further investigation.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Karin Jirström
- Department of Clinical Sciences, Oncology and Pathology, Lund University, Skåne University Hospital, Lund 221 85, Sweden.
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Zhai J, Wang Y, Yang F, Hu J, Qi Q, Zhang Y. DRP-1, ezrin and E-cadherin expression and the association with esophageal squamous cell carcinoma. Oncol Lett 2014; 8:133-138. [PMID: 24959233 PMCID: PMC4063655 DOI: 10.3892/ol.2014.2114] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 04/01/2014] [Indexed: 12/24/2022] Open
Abstract
It has been shown that death-associated protein kinase (DAPK) family and E-cadherin play significant roles in the promotion of apoptosis and the suppression of cell adhesion and migration, and are involved in tumor metastasis. Ezrin, a cytoplasmic peripheral membrane protein, has been shown to interact with E-cadherin to participate in the metastasis of tumor cells. The present study aimed to investigate the expression of DRP-1 (a member of the DAPK family), ezrin and E-cadherin in esophageal squamous cell carcinoma (ESCC), and to analyze their association with clinicopathological factors in order to explore their potential in ESCC diagnosis. The expression of these genes was studied in tissue microarrays using in situ hybridization and immunohistochemistry methods in 76 specimens of ESCC and their paracancerous normal squamous epithelium tissues. Expression was statistically analyzed with regard to clinicopathological factors using χ2 and non-parametric tests. The expression level of DRP-1 was significantly different between the ESCC and paracancerous tissues (P<0.05). The expression level was correlated with the depth of invasion and lymph node metastasis (P<0.05). Abnormal E-cadherin expression was found to be associated with a high degree of cancer differentiation and lymph node metastasis (P<0.05). A positive correlation was observed between the expression of DRP-1 and E-cadherin (P<0.05). The expression of ezrin was found to be correlated with the depth of ESCC invasion, the degree of differentiation and lymph node metastasis (P<0.05). The high expression of ezrin has been previously shown to be correlated with the low or absent expression of E-cadherin. In conclusion, in ESCC, the expression levels of DRP-1, ezrin and E-cadherin were all reduced, and this reduction or absence of expression may have been attributed to ESCC tumorigenesis and progression. Simultaneous analyses of DRP-1, ezrin and E-cadherin expression levels would be useful to determine the malignancy and metastatic potential of ESCC, and these genes are consequently of potential use as biomarkers for the diagnosis and prognosis assessment of early-stage ESCC.
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Affiliation(s)
- Jianwen Zhai
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Yanchen Wang
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Fushen Yang
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Jigang Hu
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Qingbin Qi
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Yanli Zhang
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056002, P.R. China
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Zhou J, Feng Y, Tao K, Su Z, Yu X, Zheng J, Zhang L, Yang D. The expression and phosphorylation of ezrin and merlin in human pancreatic cancer. Int J Oncol 2014; 44:2059-67. [PMID: 24728215 DOI: 10.3892/ijo.2014.2381] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 03/21/2014] [Indexed: 11/06/2022] Open
Abstract
Pancreatic carcinoma is the most common pancreatic malignancy and is associated with a very poor prognosis. Therefore, new prognostic factors and new treatment strategies are clearly needed. In this study, we retrospectively studied the levels of phosphorylated ezrin in 19 patients with pancreatic carcinoma by immunohistochemical analysis and determined the correlation between protein expression, clinicopathological characteristics and prognosis in pancreatic adenocarcinoma. We also characterized the phenotype of the overexpression of wild-type and phosphorylated ezrin and merlin in human pancreatic cancer cell lines. A significant correlation between the levels of phosphorylated ezrin 353 and ezrin 567 and the stage of pancreatic cancer was observed. Moreover, Kaplan-Meier analysis revealed that patients with high levels of phosphorylated ezrin had a significantly poorer survival rate (P<0.05). In addition, the overexpression of wild-type merlin or ezrin inhibited cell proliferation, migration and adhesion. However, the overexpression of T567D ezrin, a mutant that mimics permanent phosphorylation, promoted the proliferation, adhesion and migration of the pancreatic adenocarcinoma cell line SW1990. The overexpression of S518D merlin inhibited the growth of SW1990 and did not affect migration or adhesion. These results suggest that the phosphorylation of ezrin may contribute to the progression of pancreatic carcinoma and that the level of phosphorylated ezrin may serve as an adverse prognostic factor for pancreatic carcinoma.
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Affiliation(s)
- Jiahua Zhou
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, P.R. China
| | - Yongjiang Feng
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, P.R. China
| | - Ketao Tao
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, P.R. China
| | - Zhanhai Su
- Basic Medical Research Center, Qinghai University, Xining 810001, P.R. China
| | - Xiaojin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing 210009, P.R. China
| | - Jie Zheng
- Department of Pathology, School of Medicine, Southeast University, Nanjing 210009, P.R. China
| | - Lihua Zhang
- Department of Surgical Pathology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, P.R. China
| | - Detong Yang
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, P.R. China
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Jin T, Jin J, Li X, Zhang S, Choi YH, Piao Y, Shen X, Lin Z. Prognostic implications of ezrin and phosphorylated ezrin expression in non-small cell lung cancer. BMC Cancer 2014; 14:191. [PMID: 24629131 PMCID: PMC3985600 DOI: 10.1186/1471-2407-14-191] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Accepted: 03/05/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The cytoskeletal organizer ezrin is a member of the ezrin-radixin-moesin (ERM) family and plays important roles in not only cell motility, cell adhesion, and apoptosis, but also in various cell signaling pathways. Phosphorylation at Thr-567 and Tyr-353 are key regulatory events in the transition of the dormant to active form of ezrin. This study investigated the prognostic implications of ezrin and phosphorylated ezrin (p-ezrin) expression in non-small cell lung carcinoma (NSCLC). METHODS Ezrin and p-ezrin protein expressions were examined by immunohistochemistry in 150 NSCLC and adjacent non-tumor tissues and 14 normal lung tissues. qRT-PCR was used to determine ezrin mRNA expression levels in fresh tissues. The correlations between overexpression of ezrin and p-ezrin and the clinicopathological features of NSCLC were analyzed. The survival rates were calculated by the Kaplan-Meier method for 108 NSCLC cases. RESULTS Ezrin and ezrinThr-567 proteins showed cytosolic and membranous staining patterns; however, ezrinTyr-353 protein only showed cytosolic staining. Ezrin and p-ezrin were significantly upregulated in NSCLC compared with the normal counterparts. Increased ezrin, ezrinThr-567, and ezrinTyr-353 levels were correlated with the late stage and poor differentiation of NSCLC. However, only ezrinThr-567 was correlated with the presence of lymph node metastasis. In regard to survival, only ezrinThr-567 was related with the overall survival time of patients with NSCLC, and both ezrin and ezrinThr-567 were associated with shortened survival time for patients with early stage NSCLC. CONCLUSIONS Ezrin and p-ezrin, especially ezrinThr-567, may prove to be useful as a novel prognostic biomarker of NSCLC.
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Affiliation(s)
| | | | | | | | | | | | - Xionghu Shen
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji 133002, China.
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Ren L, Khanna C. Role of ezrin in osteosarcoma metastasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 804:181-201. [PMID: 24924175 DOI: 10.1007/978-3-319-04843-7_10] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The cause of death for the vast majority of cancer patients is the development of metastases at sites distant from that of the primary tumor. For most pediatric sarcoma patients such as those with osteosarcoma (OS), despite successful management of the primary tumor through multimodality approaches, the development of metastases, commonly to the lungs, is the cause of death. Significant improvements in long-term outcome for these patients have not been seen in more than 30 years. Furthermore, the long-term outcome for patients who present with metastatic disease is grave [1-5]. New treatment options are needed.Opportunities to improve outcomes for patients who present with metastases and those at-risk for progression and metastasis require an improved understanding of cancer progression and metastasis. With this goal in mind we and others have identified ezrin as a metastasis-associated protein that associated with OS and other cancers. Ezrin is the prototypical ERM (Ezrin/Radixin/Moesin) protein family member. ERMs function as linker proteins connecting the actin cytoskeleton and the plasma membrane. Since our initial identification of ezrin in pediatric sarcoma, an increasing understanding the role of ezrin in metastasis has emerged. Briefly, ezrin appears to allow metastatic cells to overcome a number of stresses experienced during the metastatic cascade, most notably the stress experienced as cells interact with the microenvironment of the secondary site. Cells must rapidly adapt to this environment in order to survive. Evidence now suggests a connection between ezrin expression and a variety of mechanisms linked to this important cellular adaptation including the ability of metastatic cells to initiate the translation of new proteins and to allow the efficient generation of ATP through a variety of sources. This understanding of the role of ezrin in the biology of metastasis is now sufficient to consider ezrin as an important therapeutic target in osteosarcoma patients. This chapter reviews our understanding of ezrin and the related ERM proteins in normal tissues and physiology, summarizes the expression of ezrin in human cancers and associations with clinical parameters of disease progression, reviews reports that detail a biological understanding of ezrin's role in metastatic progression, and concludes with a rationale that may be considered to target ezrin and ezrin biology in osteosarcoma.
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Affiliation(s)
- Ling Ren
- Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Rm 2144, Bethesda, MD, 20892, USA,
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Increase in ezrin expression from benign to malignant breast tumours. Cell Oncol (Dordr) 2013; 36:485-91. [DOI: 10.1007/s13402-013-0153-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/18/2013] [Indexed: 10/26/2022] Open
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Han K, Qi W, Gan Z, Shen Z, Yao Y, Min D. Prognostic value of Ezrin in solid tumors: a meta-analysis of the literature. PLoS One 2013; 8:e68527. [PMID: 23894313 PMCID: PMC3716773 DOI: 10.1371/journal.pone.0068527] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 05/30/2013] [Indexed: 11/19/2022] Open
Abstract
PURPOSE Ezrin is a cytoskeletal protein involved in tumor growth and invasion. However its prognostic value for survival in patients with solid tumor remains controversial. METHODS Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS Twenty-seven eligible trials involving 4693 patients were ultimately identified. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive Ezrin expression had an impact on overall survival (OS) [1.95, 95% confidence interval (CI) 1.60-2.39; P<0.001] in all eligible studies and progress free survival (PFS): (2.30 95% CI 1.0-3.61; P = 0.001). Similar results were also observed in subgroup analysis, according to tumor types, regions, patients' number and publication year. CONCLUSIONS Our findings suggested that Ezrin protein expression might be a factor for a poor prognosis in patients with solid tumor. So large well-designed prospective studies are now needed to confirm the clinical utility of Ezrin as an independent prognostic marker.
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Affiliation(s)
- Kun Han
- Department of Oncology, Shanghai Sixth People's Hospital East Campus, Shanghai Jiao Tong University, Shanghai, China
| | - WeiXiang Qi
- Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - ZhiHua Gan
- Department of Oncology, Shanghai Sixth People's Hospital East Campus, Shanghai Jiao Tong University, Shanghai, China
| | - Zan Shen
- Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Yao
- Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - DaLiu Min
- Department of Oncology, Shanghai Sixth People's Hospital East Campus, Shanghai Jiao Tong University, Shanghai, China
- * E-mail:
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Li H, Min D, Zhao H, Wang Z, Qi W, Zheng S, Tang L, He A, Sun Y, Yao Y, Shen Z. The Prognostic Role of Ezrin Immunoexpression in Osteosarcoma: A Meta-Analysis of Published Data. PLoS One 2013; 8:e64513. [PMID: 23805177 PMCID: PMC3689793 DOI: 10.1371/journal.pone.0064513] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 04/16/2013] [Indexed: 11/21/2022] Open
Abstract
Background The significance of ezrin immunoexpression and prognosis for osteosarcoma is still controversial. The aim was to provide a meta-analysis for ezrin immunoexpression and prognostic features of osteosarcoma patients. Methods A detailed search was made in MEDLINE, EMBASE and the Web of Knowledge for relevant original articles published in English; methodological quality of the included studies was also assessed. Two reviewers extracted data independently. Studies were pooled and summary hazard ratios (HRs) and odds ratio (ORs) with corresponding confidence intervals (CIs) were calculated. Results Final analysis of 318 patients from 5 eligible studies was performed. Combined HR of ezrin immunohistochemical staining suggested that positive immunoexpression had an unfavorable impact on osteosarcoma patients' overall survival (n = 223 in 4 studies; HR = 4.79; 95% CI: 1.50–15.30; P = 0.008) but not on event-free survival (n = 202 in 3 studies; HR = 1.59; 95% CI: 0.61–4.15; P = 0. 0.342). Combined OR of ezrin immunohistochemical staining indicated that positive immunoexpression was associated with recurrence (n = 134 in 2 studies; OR = 3.79; 95% CI: 1.49–9.64; P = 0.005) but not with serum ALP level (n = 160 in 2 studies; OR = 2.16; 95% CI: 0.09–52.50; P = 0.637) and histological response to neoadjuvant chemotherapy(n = 260 in 4 studies; OR = 0.87; 95% CI: 0.37–2.03; P = 0.740). Conclusions The results of this meta-analysis suggest that ezrin positive immunoexpression confers a higher risk of recurrence and a worse survival in osteosarcoma patients. Large prospective studies are needed to provide solid data to investigate the precise prognostic significance of ezrin.
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Affiliation(s)
- Hongtao Li
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Daliu Min
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Hui Zhao
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Zhiyu Wang
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Weixiang Qi
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Shuier Zheng
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Lina Tang
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Aina He
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Yuanjue Sun
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Yang Yao
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Zan Shen
- Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
- * E-mail:
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Chen QY, Xu W, Jiao DM, Wu LJ, Song J, Yan J, Shi JG. Silence of ezrin modifies migration and actin cytoskeleton rearrangements and enhances chemosensitivity of lung cancer cells in vitro. Mol Cell Biochem 2013; 377:207-18. [PMID: 23435957 DOI: 10.1007/s11010-013-1586-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Accepted: 02/08/2013] [Indexed: 01/27/2023]
Abstract
Ezrin, primarily acts as a linker between the plasma membrane and the cytoskeleton, is involved in many cellular functions, including regulation of actin cytoskeleton, control of cell shape, adhesion, motility, and modulation of signaling pathways. Although ezrin is now recognized as a key component in tumor metastasis, its roles and the underlying mechanisms remain unclear. In the present study, we chose highly metastatic human lung carcinoma 95D cells, which highly express the ezrin proteins, as a model to examine the functional roles of ezrin in tumor suppression. An ezrin-silenced 95D cell line was established using lentivirus-mediated short hairpin RNA method. CCK-8 assay and soft agar assay analysis showed that downregulation of ezrin significantly suppressed the tumorigenicity and proliferation of 95D cells in vitro. cell migration and invasion studies showed that ezrin-specific deficiency in the cells caused the substantial reduction of the cell migration and invasion. In parallel, it also induced rearrangements of the actin cytoskeleton. Flow cytometry assay showed that changes in the ezrin protein level significantly affected the cell cycle distribution and eventual apoptosis. Furthermore, further studies showed that ezrin regulated the expression level of E-cadherin and CD44, which are key molecules involved in cell growth, migration, and invasion. Meanwhile, the suppression of ezrin expression also sensitized cells to antitumor drugs. Altogether, our results demonstrated that ezrin played an important role in the tumorigenicity and metastasis of lung cancer cells, which will benefit the development of therapeutic strategy for lung cancer.
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Affiliation(s)
- Qing-Yong Chen
- Department of Respiratory Disease, The 117th Hospital of PLA, Hang Zhou, People's Republic of China.
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Tobo T, Hirahashi M, Yao T, Aishima S, Oda Y. Ezrin expression and its phosphorylation in gastric carcinoma with lymphoid stroma and Epstein-Barr virus infection. Mol Clin Oncol 2012; 1:220-224. [PMID: 24649150 DOI: 10.3892/mco.2012.56] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 12/05/2012] [Indexed: 12/13/2022] Open
Abstract
Gastric carcinoma with lymphoid stroma (GCLS) is a unique variant of gastric carcinoma that represents prominent lymphocytic infiltration and is correlated with Epstein-Barr virus (EBV) infection. Ezrin expression and activation are crucial in tumor metastasis and induce cell migration of EBV-related nasopharyngeal carcinomas. Using immunohistochemical methods, the expression of total and phosphorylated ezrin (p-ezrin), Thr567, was examined in 104 GCLS cases, including 78 EBV-positive and 26 EBV-negative cases, as well as 29 non-GCLS cases. Positive ezrin expression was detected to be at markedly higher levels in GCLS compared to non-GCLS (P<0.0001). Furthermore, ezrin expression was detected to be at higher levels in EBV-positive compared to EBV-negative GCLS (P=0.0294). High expression of p-ezrin in GCLS was associated with positive lymph node metastasis (P=0.0187). In summary, these results demonstrated that ezrin overexpression is correlated with the histologic characteristics of GCLS and EBV infection. Phosphorylation of ezrin may, therefore, contribute to lymph node metastasis in GCLS.
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Affiliation(s)
- Taro Tobo
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Minako Hirahashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Shinichi Aishima
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
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Expression and Clinical Significance of Ezrin in Non–Small-Cell Lung Cancer. Clin Lung Cancer 2012; 13:196-204. [DOI: 10.1016/j.cllc.2011.04.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2011] [Revised: 04/05/2011] [Accepted: 04/19/2011] [Indexed: 11/21/2022]
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Jaroensong T, Endo Y, Lee SJ, Kamida A, Mochizuki M, Nishimura R, Sasaki N, Nakagawa T. Effects of transplantation sites on tumour growth, pulmonary metastasis and ezrin expression of canine osteosarcoma cell lines in nude mice. Vet Comp Oncol 2011; 10:274-82. [PMID: 22236104 DOI: 10.1111/j.1476-5829.2011.00294.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
To determine the influence of the transplantation site of canine osteosarcoma (OS) cell lines on tumour growth and pulmonary metastasis, three OS cell lines were transplanted into nude mice via subcutaneous (SC), intratibial (IT) or intravenous (IV) injection. IT-xenografts exhibited greater potential for developing primary masses and pulmonary metastasis than SC-xenografts. In IT and IV xenografts, lung micrometastases along with phosphorylated ezrin-radixin-moesin (p-ERM) overexpression were found in mice xenografted with HMPOS and OOS cells after 1 week and metastasis was found with decreased p-ERM expression at later time points. The expression of ezrin and p-ERM in the primary tumours of IT-xenografted mice was higher than those in SC-xenografted mice with HMPOS and OOS cells. The results suggest that the orthotopic transplantation site plays an important role in the spontaneous metastasis of canine OS and that ezrin phosphorylation may be involved in the early metastatic mechanism of canine OS cells.
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Affiliation(s)
- T Jaroensong
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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Athanasopoulou A, Aroukatos P, Nakas D, Repanti M, Papadaki H, Bravou V. Decreased ezrin and paxillin expression in human urothelial bladder tumors correlate with tumor progression. Urol Oncol 2011; 31:836-42. [PMID: 21868260 DOI: 10.1016/j.urolonc.2011.07.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 06/29/2011] [Accepted: 07/07/2011] [Indexed: 12/01/2022]
Abstract
OBJECTIVES F-actin binding proteins ezrin and paxillin are involved in cell adhesion and cell migration/invasion. The aim of the study was to investigate their role in urothelial bladder carcinogenesis. MATERIALS AND METHODS Expression of ezrin and paxillin was studied by immunohistochemistry in 104 and 96 cases of urothelial bladder tumors, respectively. Correlations with clinicopathologic data and expression of p53, E-cadherin, and β-catenin were examined. RESULTS Positive ezrin and paxillin protein expression was found in 99% and 93.7% of cases, respectively. Membranous expression of ezrin was significantly lower in high grade tumors and correlated with invasion. Multivariate analysis showed that ezrin is an independent predictor of muscularis propria invasion. Paxillin expression was significantly decreased in urothelial carcinomas compared with tumors of low malignant potential and low paxillin levels also correlated with advancing tumor stage and invasion. A statistically significant correlation was found between membranous ezrin and E-cadherin as well as between ezrin and paxillin expression in urothelial tumors. CONCLUSIONS Down-regulation of ezrin and paxillin in urothelial bladder tumors is associated with aggressive tumor features and invasiveness.
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Affiliation(s)
- Afrodite Athanasopoulou
- Department of Anatomy-Histology-Embryology, School of Medicine, University of Patras, Patras, Greece
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Abdou AG, Maraee AH, El-Sayed EMM, Elnaidany NF. Immunohistochemical expression of ezrin in cutaneous basal and squamous cell carcinomas. Ann Diagn Pathol 2011; 15:394-401. [PMID: 21849257 DOI: 10.1016/j.anndiagpath.2011.05.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2011] [Revised: 05/16/2011] [Accepted: 05/18/2011] [Indexed: 02/01/2023]
Abstract
Ezrin is a member of the ezrin-radixin-moesin family of proteins, which link the actin-containing cytoskeleton to the plasma membrane. Overexpression of ezrin protein is correlated with the metastatic potential in several cancers. Little is known about the distribution of ezrin in normal epidermis and nonmelanoma skin cancer; therefore, in the current study, we examined the immunohistochemical expression of ezrin in normal skin (10 biopsies) and epithelial skin tumors (25 basal cell carcinoma [BCC] and 20 squamous cell carcinoma [SCC]). Ezrin was expressed in epidermis of all normal controls with a prominent membranous pattern compared with 93.3% positivity in malignant cases with a significant higher intensity (assessed by H score) in favor of the latter (P = .002). Cytoplasmic expression of ezrin either alone or associated with membranous expression was both seen in BCC and SCC. The median value of H score in SCC (160) cases was higher than that in BCC (60). H score values of ezrin expression in BCC was significantly higher in tumors arising in sites other than the head and neck (P = .04). In SCC, the intensity of ezrin expression tended to be associated with advanced stage (P = .08). Our study demonstrated the probable tumorigenic role of ezrin in epithelial skin tumor formation. It may enhance local invasion or metastasis of epithelial skin tumors, which necessitates further larger study to clarify. The intensity rather than the pattern of ezrin expression had a more probable impact on the tumor behavior.
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Affiliation(s)
- Asmaa Gaber Abdou
- Pathology Department, Faculty of Medicine, Menofiya university, Shebein Elkom, 32511 Egypt.
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Emmanuel C, Gava N, Kennedy C, Balleine RL, Sharma R, Wain G, Brand A, Hogg R, Etemadmoghadam D, George J, Birrer MJ, Clarke CL, Chenevix-Trench G, Bowtell DDL, Harnett PR, deFazio A. Comparison of expression profiles in ovarian epithelium in vivo and ovarian cancer identifies novel candidate genes involved in disease pathogenesis. PLoS One 2011; 6:e17617. [PMID: 21423607 PMCID: PMC3057977 DOI: 10.1371/journal.pone.0017617] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Accepted: 02/02/2011] [Indexed: 12/30/2022] Open
Abstract
Molecular events leading to epithelial ovarian cancer are poorly understood but
ovulatory hormones and a high number of life-time ovulations with concomitant
proliferation, apoptosis, and inflammation, increases risk. We identified genes
that are regulated during the estrous cycle in murine ovarian surface epithelium
and analysed these profiles to identify genes dysregulated in human ovarian
cancer, using publically available datasets. We identified 338 genes that are
regulated in murine ovarian surface epithelium during the estrous cycle and
dysregulated in ovarian cancer. Six of seven candidates selected for
immunohistochemical validation were expressed in serous ovarian cancer,
inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium.
Most were overexpressed in ovarian cancer compared with ovarian surface
epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2
were expressed as highly in fallopian tube epithelium as in ovarian cancer. We
prioritised the 338 genes for those likely to be important for ovarian cancer
development by in silico analyses of copy number aberration and
mutation using publically available datasets and identified genes with
established roles in ovarian cancer as well as novel genes for which we have
evidence for involvement in ovarian cancer. Chromosome segregation emerged as an
important process in which genes from our list of 338 were over-represented
including two (BUB1, NCAPD2) for which there
is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface
epithelium in proestrus and predicted to have a driver mutation in ovarian
cancer, was examined in a larger cohort of serous ovarian cancer where patients
with lower NUAK2 expression had shorter overall survival. In conclusion,
defining genes that are activated in normal epithelium in the course of
ovulation that are also dysregulated in cancer has identified a number of
pathways and novel candidate genes that may contribute to the development of
ovarian cancer.
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Affiliation(s)
- Catherine Emmanuel
- Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia.
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Sequential Dose-Dense Doxorubicin and Ifosfamide in Advanced Soft-Tissue Sarcoma Patients in an Out-Patient-Basis Schedule. Sarcoma 2011; 2011:984340. [PMID: 21785570 PMCID: PMC3140044 DOI: 10.1155/2011/984340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2010] [Revised: 04/05/2011] [Accepted: 05/04/2011] [Indexed: 11/28/2022] Open
Abstract
Aims. This phase II study explored activity/safety of front-line dose-dense chemotherapy in high-grade STS (soft tissue sarcoma) patients and tested ezrin as prognostic factor. Patients and Methods. The protocol consisted of three cycles of doxorubicin (DOXO) 30 mg/m2 on days 1–3 every 2 weeks, followed by three cycles of ifosfamide (IFO) 2.5 g/m2 two hours a day on days 1–5 every 3 weeks, with GCSF support. Ezrin was assessed immunohistochemically. Results. Twenty patients, 13 metastatic and 7 locally advanced, were enrolled. Median age was 39 years (25–60). Median dose intensities were 42 mg/m2/week and 3.6 g/m2/week for DOXO and IFO, respectively. Grade 3/4 toxicities occurred in 18 patients. Response rate was 15% (3 of 20) by RECIST. Patients younger than 45 years with locally advanced disease and synovial histology presented longer survival. A trend towards longer survival was observed among ezrin-positive patients. Conclusions. This dose-dense schedule should not be routinely used due to its high frequency of toxic events; however, a sequential strategy with DOXO and IFO may benefit selected patients and should be further explored with lower doses. The role of ezrin as a prognostic marker should be confirmed in a larger group of patients.
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Huang HY, Li CF, Fang FM, Tsai JW, Li SH, Lee YT, Wei HM. Prognostic implication of ezrin overexpression in myxofibrosarcomas. Ann Surg Oncol 2010; 17:3212-3219. [PMID: 20585869 DOI: 10.1245/s10434-010-1185-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2010] [Indexed: 11/18/2022]
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. METHODS Ezrin immunostain could be assessed from tissue microarrays of 78 cases of primary localized myxofibrosarcomas and correlated with clinicopathological factors and patient survival. In two myxofibrosarcoma cell lines, ezrin mRNA expression was measured by real-time reverse transcriptase-polymerase chain reaction and the endogenous expression and activating phosphorylation of ezrin protein analyzed by Western blot test. RESULTS Ezrin overexpression was significantly associated with remarkable tumor necrosis (P = 0.025), increased histological grades (P = 0.037), advanced American Joint Committee on Cancer stages (P = 0.034), and higher mitotic rate (P < 0.001). Importantly, ezrin overexpression independently predicted inferior metastasis-free survival (P = 0.012, risk ratio = 4.083) and disease-specific survival (P = 0.0337, risk ratio = 4.537). The mRNA and total protein of ezrin in various cells were comparable in the expression level. Despite variation in abundance, phosphorylated ezrin at threonine(567) was detectable in myxofibrosarcoma cell lines but not in fibroblasts. CONCLUSIONS 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.
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Affiliation(s)
- Hsuan-Ying Huang
- Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung County 833, Taiwan.
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Abstract
BACKGROUND Metastasis is an important prognostic factor among patients with osteosarcoma. It has been reported that ezrin is important in enabling metastasis and that CD44 expression leads to functional increases in ezrin activation. OBJECTIVE The aim of this study was to correlate ezrin and CD44 expression with prognosis. SAMPLES AND METHODS Patients with a diagnosis of osteosarcoma who had been treated at Hospital de Cancer de Barretos, Barretos, SP, Brazil, between 2000 and 2005 were selected from the Hospital Tumor Registry. Fifty-two patients and, among these, 34 surgical biopsy specimens of osteosarcoma before chemotherapy were reviewed by the Pathology Department. Ezrin and CD44H protein expression was evaluated using immunohistochemistry on the initial biopsy for these 34 samples. RESULTS Most patients (76%) were ezrin-positive in cytoplasm and membrane (38.2%); 58.9% presented high-intensity staining and 50.0% had high scores. Half of the patients were CD44H-positive, predominantly in cytoplasm (38.2%); 20.6% presented staining in more than 50% of the cells. None of the markers showed associations with any of the clinicopathologic variables studied. Among the ezrin-positive patients, the 5-year survival rate was 12.8%, whereas it was 41.7% among ezrin-negative patients (P=0.121). The interaction between ezrin and poor histologic response among nonmetastatic patients showed an association with relapse-free 5-year survival of 100% versus 12.7% (P=0.042). The overall survival rates for CD44-positive and negative patients were similar (21.5% and 25.3%, respectively) (P=0.676). CONCLUSIONS Neither CD44H nor ezrin immunoexpression could predict the prognosis for patients with osteosarcoma in our small sample.
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SÖDERSTRÖM MIRVA, PALOKANGAS TUIRE, VAHLBERG TERO, BÖHLING TOM, ARO HANNU, CARPEN OLLI. Expression of ezrin, Bcl-2, and Ki-67 in chondrosarcomas. APMIS 2010; 118:769-76. [DOI: 10.1111/j.1600-0463.2010.02656.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Pérez P, Aguilera S, Olea N, Alliende C, Molina C, Brito M, Barrera MJ, Leyton C, Rowzee A, González MJ. Aberrant localization of ezrin correlates with salivary acini disorganization in Sjogren's Syndrome. Rheumatology (Oxford) 2010; 49:915-23. [PMID: 20185532 DOI: 10.1093/rheumatology/keq033] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES To analyse whether the alterations in the structure and organization of microvilli in salivary acinar cells from SS patients are linked to changes in the expression and/or cellular localization of ezrin. METHODS Salivary gland (SG) acini from controls and SS patients were used to evaluate ezrin expression by western blot and localization of total and activated (phospho-Thr567) ezrin by IF and EM. RESULTS In acini from control labial SGs, ezrin was located predominantly at the apical pole and to a lesser extent at the basal region of these cells. Conversely, in acini extracts from SS patients, ezrin showed significantly elevated levels, which were accompanied with localization mostly at the basal region. Moreover, F-actin maintained its distribution in both the apical region and basolateral cortex; however, it was also observed in the acinar cytoplasm. Phospho-ezrin (active form) was located exclusively at the apical pole of acinar cells from control subjects and abundantly located at the basal cytoplasm in SS samples. These results were confirmed by immunogold studies. CONCLUSIONS The decrease of ezrin and phospho-ezrin at the apical pole and the cytoplasmic redistribution of F-actin suggest an altered interaction between the F-actin-cytoskeleton and plasma membrane in SS patient acini, which may explain the microvilli disorganization. These alterations could eventually contribute to SG hyposecretion in SS patients.
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Affiliation(s)
- Paola Pérez
- Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70061, Santiago 7, Chile.
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Hao L, Xie P, Li H, Li G, Xiong Q, Wang Q, Qiu T, Liu Y. Transcriptional alteration of cytoskeletal genes induced by microcystins in three organs of rats. Toxicon 2010; 55:1378-86. [PMID: 20184910 DOI: 10.1016/j.toxicon.2010.02.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 02/07/2010] [Accepted: 02/16/2010] [Indexed: 10/19/2022]
Abstract
This study explored the mechanisms of toxicity of microcystins by measuring the transcription levels of nine cytoskeletal genes (actin, tubulin, vimentin, ezrin, radixin, moesin, MAP1b, tau, stathmin) in the liver, kidney and spleen of male Wistar rats treated with microcystins at a dose of 80 microg MC-LReq kg(-1) bw. Microcystins disrupted the transcriptional homeostasis of cytoskeletal genes in these organs. Changes in the transcription of four genes (beta-actin, ezrin, radixin and tau) in liver, one gene (stathmin) in kidney, and one gene (radixin) in spleen were significantly correlated with the tissue concentration of microcystins. However, the influences on the transcription of most genes we studied were greater in the liver than in the kidney or spleen. The effects of microcystins on the transcription of cytoskeletal genes may explain some of the morphological and pathological changes observed in these organs and provide new information on the hepatotoxicity of these compounds. Additionally, transcriptional changes in tumor-associated cytoskeletal genes (ezrin, moesin and stathmin) that were observed in the present study provide a possible clue to the tumor-promoting potential of microcystins and their influences on the transcription of MAP1b and tau imply possible neurological toxicity of microcystins in vertebrates.
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Affiliation(s)
- Le Hao
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory for Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, The Chinese Academy of Sciences, Donghu South Road 7, Wuhan 430072, People's Republic of China
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Wei YC, Li CF, Yu SC, Chou FF, Fang FM, Eng HL, Uen YH, Tian YF, Wu JM, Li SH, Huang WW, Li WM, Huang HY. Ezrin overexpression in gastrointestinal stromal tumors: an independent adverse prognosticator associated with the non-gastric location. Mod Pathol 2009; 22:1351-1360. [PMID: 19648886 DOI: 10.1038/modpathol.2009.107] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ezrin, a member of the ezrin-radixin-moesin family, acts as a link between the cell membrane and actin cytoskeleton to integrate cell adhesion-mediated signaling. It implicates tumor progression, metastatic dissemination, and adverse outcomes in several cancer types, including pediatric and adult sarcomas. Although ezrin upregulation was shown by cDNA expression profiling, no study has systematically evaluated the significance of ezrin expression in a large cohort of gastrointestinal stromal tumors (GISTs). Ezrin immunostaining was carried out on tissue microarrays of primary GISTs and assessable in 347 cases, 188 of which were successfully evaluated for mutation variants of KIT and PDGFRA receptor tyrosine kinase (RTK) genes by sequencing with or without screening by denatured high-performance liquid chromatography. These GISTs with known RTK genotypes were dichotomized into two prognostically different groups. The endogenous expression and phosphorylation of ezrin in GIST cell lines were analyzed by western blotting. By immunohistochemistry, ezrin overexpression was present in 66% of GISTs and significantly associated with the non-gastric location (P=0.002) and decreased disease-free survival (P=0.032, univariately). However, it was not related to the National Institute of Health (NIH) risk category, Ki-67 labeling index, RTK genotypes, and other variables. In multivariate analyses, ezrin overexpression remained independently predictive of adverse outcome (P=0.008, risk ratio=2.363), together with Ki-67 labeling index >5% (P<0.001, risk ratio=3.581), high-risk category (P<0.001, risk ratio=2.156), and the non-gastric location (P=0.029, risk ratio=1.899). Despite the variation in the ezrin expression level, phosphorylated ezrin at threonine(567) was only detectable in GIST882 and GIST48 cells, but not in colonic smooth muscle cells. In conclusion, ezrin is frequently overexpressed in GISTs, especially those arising from the non-gastric sites. Given that its impact is independent of the NIH risk category, cell proliferation, and tumor location, ezrin immunoreactivity represents a valuable prognostic adjunct of GISTs, suggesting a causative role in conferring an aggressive phenotype.
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Affiliation(s)
- Yu-Ching Wei
- Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Kim C, Shin E, Hong S, Chon HJ, Kim HR, Ahn JR, Hong MH, Yang WI, Roh JK, Rha SY. Clinical value of ezrin expression in primary osteosarcoma. Cancer Res Treat 2009; 41:138-44. [PMID: 19809563 DOI: 10.4143/crt.2009.41.3.138] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Accepted: 06/01/2009] [Indexed: 01/21/2023] Open
Abstract
PURPOSE Ezrin is a membrane cytoskeletal linker protein and it is known to be associated with metastasis of primary osteosarcoma. The aim of this study is to determine the relationship between an ezrin expression and several key clinical parameters and to elucidate its potential prognostic value for patients with osteosarcoma. MATERIALS AND METHODS Seventy patients with histologically confirmed osteosarcoma and who had no distant metastasis were enrolled between 1995 and 2005 at Yonsei Cancer Center, Severance Hospital, Korea. The clinical parameters were retrospectively reviewed and immunohistochemical staining (IHC) for ezrin was performed using the surgically resected specimens. RESULTS Of the 70 tumor specimens, 39 (55.7%) revealed an ezrin expression. More of an osteoblastic histology and an elevated initial ALP level were observed in the ezrin positive patients than in the ezrin negative patients (p=0.008 and 0.001, respectively). The proportion of patients who favorably responded to neoadjuvant chemotherapy (≥or=90% necrosis) was significantly higher in the group of ezrin positive patients than that in the group of ezrin negative patient (72.2% vs 45.2%, respectively, p=0.024). The ezrin positive patients showed more frequent recurrence than did the ezrin negative patients (64.1% vs 35.5%, respectively, p=0.017). The patients with an ezrin expression also demonstrated poorer survival than did those patients without ezrin expression (5-year EFS: 31.7% vs 61.3%, respectively, p=0.023, 5-year OS: 53.4% vs 71.0%, respectively, p=0.022). When comparing EFS according to both an ezrin expression and chemoresponsiveness, there were trends that the ezrin negative/chemoresponsive group showed the best 5-year EFS (71.4%), followed by the ezrin negative/chemoresistant group (52.9%), the ezrin positive/chemoresponsive group (38.1%) and the ezrin positive/chemoresistant group (13.6%). These trends were statistically significant (p=0.036). CONCLUSION The expression of ezrin by IHC staining was found in 55.7% of the patients with metastasis-free osteosarcoma. Immunoreactivity to ezrin is a negative prognostic factor for survival for the patients suffering with osteosarcoma. Identifying an ezrin expression might offer a valuable piece of information when treating patients with primary osteosarcoma.
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Affiliation(s)
- Chan Kim
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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Sugitani M, Aramaki O, Kikuchi K, Sheikh A, Oinuma T, Mamiya T, Takayama T, Nemoto N. Two cases of primary malignant fibrous histiocytoma of the liver: immunohistochemical expression of ezrin and its relationship with prognosis. Acta Histochem Cytochem 2009; 42:83-8. [PMID: 19617955 PMCID: PMC2711395 DOI: 10.1267/ahc.09002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Accepted: 04/01/2009] [Indexed: 02/03/2023] Open
Abstract
Malignant fibrous histiocytoma (MFH) as soft tissue sarcoma would not be especially noteworthy, but primary hepatic MFH reports are extremely rare. Herein, we report ezrin expression in tumor tissues from two primary hepatic MFH cases with different prognoses. Cases 1 and 2 were both women, ages 45 and 70 years, respectively. Case 1 had an 11×10 cm liver tumor in segment (S) 3, and case 2 had two liver tumors, 12×8 cm in S5 and 10×7 cm in S8. Neither had any other systemic tumors. Cases 1 and 2 survived for two year and ten months and for eight and a half months, respectively, after the initial tumor resection. Microscopically, the tumors of these two cases were similar and showed proliferation of atypical cells, including spindle, pleomorphic and multi-nucleated giant cells arranged in storiform, sheet and/or fascicle patterns, with scattered foci of inflammatory cells, indicating MFH. Ezrin expression in tumor tissue from case 1 was sparse, whereas that of case 2 showed strong ezrin expression in many tumor cells. The present results indicate ezrin immunoreactivity in primary hepatic MFH to correlate possible with prognosis, which is consistent with reports on some other types of malignancies.
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Affiliation(s)
| | - Osamu Aramaki
- Department of Pathology, Nihon University School of Medicine
- Department of Digestive Surgery, Nihon University School of Medicine
| | - Kentaro Kikuchi
- Department of Pathology, Nihon University School of Medicine
| | | | | | - Takao Mamiya
- Department of Digestive Surgery, Nihon University School of Medicine
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Federici C, Brambilla D, Lozupone F, Matarrese P, de Milito A, Lugini L, Iessi E, Cecchetti S, Marino M, Perdicchio M, Logozzi M, Spada M, Malorni W, Fais S. Pleiotropic function of ezrin in human metastatic melanomas. Int J Cancer 2009; 124:2804-12. [PMID: 19235924 DOI: 10.1002/ijc.24255] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors.
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Affiliation(s)
- Cristina Federici
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy
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Wang HJ, Zhu JS, Zhang Q, Sun Q, Guo H. High level of ezrin expression in colorectal cancer tissues is closely related to tumor malignancy. World J Gastroenterol 2009; 15:2016-9. [PMID: 19399936 PMCID: PMC2675094 DOI: 10.3748/wjg.15.2016] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the ezrin expression in normal colorectal mucosa and colorectal cancer tissues, and study the correlation between ezrin expression in colorectal cancer tissues and tumor invasion and metastasis.
METHODS: Eighty paraffin-embedded cancer tissue samples were selected from primary colorectal adenocarcinoma. Twenty-eight patients had well-differentiated, 22 had moderately differentiated and 30 had poorly differentiated adenocarcinoma. Forty-five patients and 35 patients had lymph node metastasis. Forty-five patients were of Dukes A to B stage, and 35 were of C to D stage. Another 22 paraffin-embedded tissue blocks of normal colorectal epithelium (> 5 cm away from the edge of the tumor) were selected as the control group. All patients with colorectal cancer were treated surgically and diagnosed histologically, without preoperative chemotherapy or radiotherapy. The immunohistochemistry was used to detect the ezrin expression in paraffin-embedded normal colorectal mucosa tissues and colorectal cancer tissue samples.
RESULTS: Ezrin expression in colorectal cancer was significantly higher than in normal colorectal mucosa (75.00% vs 9.09%, P < 0.01), and there was a close relationship between ezrin expression and the degree of tumor differentiation, lymph node metastasis and Dukes stage (88.46% vs 50.00%, P < 0.01; 94.28% vs 51.11%, P < 0.01; 94.28% vs 51.11%, P < 0.01).
CONCLUSION: Ezrin expression is obviously higher in colorectal cancer tissues than in normal colorectal mucosa tissues, and the high level of ezrin expression is closely related to the colorectal cancer invasion and metastasis process.
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Osawa H, Smith CA, Ra YS, Kongkham P, Rutka JT. The role of the membrane cytoskeleton cross-linker ezrin in medulloblastoma cells. Neuro Oncol 2008; 11:381-93. [PMID: 19088174 DOI: 10.1215/15228517-2008-110] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Medulloblastoma is a highly malignant brain tumor that occurs predominantly in children. The molecular pathogenesis of medulloblastoma is under investigation. Previously, we used complementary DNA microarray analysis to compare patterns of gene expression in medulloblastoma samples versus normal cerebellum. The cytoskeletal protein ezrin was found to be overexpressed in medulloblastoma compared with normal cerebellum, an observation that was further validated by immunohistochemistry and real-time PCR analysis. To assess the role of ezrin in medulloblastoma, we studied ezrin's role in medulloblastoma migration, invasion, and adhesion. Western blotting and immunofluorescence showed high expression of ezrin in four medulloblastoma cell lines, and ezrin was primarily localized to filopodia. Ezrin-specific small interfering RNA suppressed the formation of filopodia and in vitro migration, invasion, and adhesion. We also used a stably transfected medulloblastoma cell line to study the effect of ezrin overexpression. We showed that high expression of ezrin promotes filopodia formation and in vitro invasion. Finally, athymic mice implanted with ezrin-overexpressing DAOY medullo-blastoma cell clones in the cerebellum showed shortened survival compared with controls. These findings suggest that, in addition to other cytoskeletal proteins, ezrin plays an important role in medulloblastoma adhesion, migration, and invasion.
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Affiliation(s)
- Hirokatsu Osawa
- Division of Neurosurgery, The Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
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Yoon KJ, Phelps DA, Bush RA, Remack JS, Billups CA, Khoury JD. ICAM-2 expression mediates a membrane-actin link, confers a nonmetastatic phenotype and reflects favorable tumor stage or histology in neuroblastoma. PLoS One 2008; 3:e3629. [PMID: 18978946 PMCID: PMC2575377 DOI: 10.1371/journal.pone.0003629] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2008] [Accepted: 10/13/2008] [Indexed: 11/18/2022] Open
Abstract
The actin cytoskeleton is a primary determinant of tumor cell motility and metastatic potential. Motility and metastasis are thought to be regulated, in large part, by the interaction of membrane proteins with cytoplasmic linker proteins and of these linker proteins, in turn, with actin. However, complete membrane-to-actin linkages have been difficult to identify. We used co-immunoprecipitation and competitive peptide assays to show that intercellular adhesion molecule-2 (ICAM-2)/alpha-actinin/actin may comprise such a linkage in neuroblastoma cells. ICAM-2 expression limited the motility of these cells and redistributed actin fibers in vitro, and suppressed development of disseminated tumors in an in vivo model of metastatic neuroblastoma. Consistent with these observations, immunohistochemical analysis demonstrated ICAM-2 expression in primary neuroblastoma tumors exhibiting features that are associated with limited metastatic disease and more favorable clinical outcome. In neuroblastoma cell lines, ICAM-2 expression did not affect AKT activation, tumorigenic potential or chemosensitivity, as has been reported for some types of transfected cells. The observed ICAM-2-mediated suppression of metastatic phenotype is a novel function for this protein, and the interaction of ICAM-2/alpha-actinin/actin represents the first complete membrane-linker protein-actin linkage to impact tumor cell motility in vitro and metastatic potential in an in vivo model. Current work focuses on identifying specific protein domains critical to the regulation of neuroblastoma cell motility and metastasis and on determining if these domains represent exploitable therapeutic targets.
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Affiliation(s)
- Karina Jin Yoon
- Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Palou J, Algaba F, Vera I, Rodriguez O, Villavicencio H, Sanchez-Carbayo M. Protein expression patterns of ezrin are predictors of progression in T1G3 bladder tumours treated with nonmaintenance bacillus Calmette-Guérin. Eur Urol 2008; 56:829-36. [PMID: 18926620 DOI: 10.1016/j.eururo.2008.09.062] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2008] [Accepted: 09/30/2008] [Indexed: 11/25/2022]
Abstract
BACKGROUND Bacillus Calmette-Guérin (BCG) is a standard treatment for reducing tumour recurrence and delaying progression of high-risk, non-muscle-invasive bladder tumours. However, it is not clear yet which patients are more likely to be responders to BCG. OBJECTIVE To evaluate the role of ezrin expression in bladder cancer (BCa) progression in T1G3 bladder tumours treated with BCG. DESIGN, SETTING, AND PARTICIPANTS Ezrin protein expression patterns were analysed on tumour specimens belonging to 92 patients with T1G3 non-muscle-invasive BCa undergoing nonmaintenance BCG treatment. Re-resection was not performed. The median follow-up was 90.5 mo (range: 3.0-173.0). A specific tissue array was created containing three representative cores of each of the tumour specimens belonging to these patients. MEASUREMENTS Ezrin protein expression patterns were assessed by immunohistochemistry on this tissue array. Proliferation rates were assessed by means of Ki67 staining. Recurrence, progression into muscle-invasive tumours, and disease-specific overall survival (OS) rates were analysed using univariate and multivariate tests. RESULTS AND LIMITATIONS Among the 92 patients analysed, 40 recurred (43.5%), 17 progressed (18.5%), and 14 died of the disease (15.2%). Log-rank survival analyses revealed that an ezrin membrane expression <20% was significantly associated with increased progression (p=0.009) and shorter disease-specific OS (p=0.006). Multivariate analyses showed that ezrin was an independent prognostic marker of progression (p=0.031) and disease-specific survival (p=0.035). Interestingly, the low ezrin membrane expression correlated with high proliferation rates (p=0.033). CONCLUSIONS Immunohistochemistry analyses revealed that the membrane expression of ezrin is associated with the clinical outcome of patients with T1G3 tumours undergoing BCG treatment. Protein expression patterns of ezrin were associated with tumour progression in T1G3 disease. The differential expression of ezrin distinguished patients responding to BCG from those who may require a more aggressive therapeutic approach.
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Prognostic value of tumor microinvasion and metalloproteinases expression in intracranial pediatric ependymomas. J Neuropathol Exp Neurol 2008; 67:911-20. [PMID: 18716553 DOI: 10.1097/nen.0b013e318184f413] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Ependymomas are common pediatric intracranial neoplasms that often appear well circumscribed on imaging but may recur when they are treated by surgical resection alone. The current World Health Organization histological grading system does not accurately predict clinical behavior. The aim of this study was to identify histological and immunohistochemical features that correlate with clinical course in patients with ependymomas treated by gross total resection. We analyzed 41 pediatric ependymomas for microinvasion and correlated immunostaining for the metalloproteinase (MMP)-2 and MMP14 and for ezrin and bcl-2 with clinical outcome. Gross total resection had a significantly positive effect on overall survival and progression-free survival. In 28 patients who underwent gross total resection, microinvasion correlated with poor overall survival (p = 0.003) and progression-free survival (p = 0.03). Gross totally resected tumors with high expression of MMP2 and MMP14 had significantly shorter overall survival. Ezrin staining identified tumor cells invading the adjacent white matter that were not identified by routine stains, but Ezrin staining and bcl-2 staining did not provide strong prognostic correlations. The data indicate that tumor microinvasion into adjacent brain and tumor expression of MMP2 and MMP14 predict both overall and progression-free survival in pediatric ependymomas, and these are useful prognostic markers that may help stratify patients for adjuvant therapies.
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Li YF, Hu W, Fu SQ, Li JD, Liu JH, Kavanagh JJ. Aromatase inhibitors in ovarian cancer: is there a role? Int J Gynecol Cancer 2008; 18:600-14. [PMID: 17894799 DOI: 10.1111/j.1525-1438.2007.01075.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Estrogen plays a role in ovarian tumorigenesis. Aromatase is the enzyme required for the synthesis of estrogen via conversion of androgen to estrogen, which is the major source of estrogen in postmenopausal women. Aromatase is present in normal ovaries and other tissues (e.g., fat and muscle) as well as in 33-81% tumor tissues of ovarian cancer. Aromatase inhibitors (AIs) block estrogen synthesis by inhibiting aromatase activity. In patients with recurrent ovarian cancer, single-agent AI therapy has been shown to elicit clinical response rates of up to 35.7% and stable disease rates of 20-42%. Given the limited treatment options for recurrent ovarian cancer and the favorable safety profile and convenient use, AI is a rational option for prolonging platinum-free interval in recurrent ovarian cancer. Further studies are required to determine the efficacy of combination treatment with AIs and biological agents, determine the benefit of AIs for treating special types of ovarian cancer (e.g., endometrioid type), and identify biomarkers for targeted patient selection. This review summarizes the current epidemiologic, preclinical, and clinical data regarding estrogen's role in ovarian cancer, the expression and regulation of aromatase in this disease, the development and characteristics of the three generations of AIs, and the preclinical and clinical studies of AIs in the treatment of ovarian cancer.
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Affiliation(s)
- Y F Li
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230, USA
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Abstract
Identification of the key regulatory molecules in metastasis is crucial for understanding tumor dissemination and for the development of novel interventions. The recent identification of ezrin as a necessary component in the metastasis of osteosarcoma and rhabdomyosarcoma is, therefore, an important advance. Ezrin has been implicated in many roles, for example, as a conduit for signals between metastasis-associated cell-surface molecules and signal transduction components. This suggests that ezrin and, potentially, other members of the ERM (ezrin-radixin-moesin) family have key roles in the coordination of signals and cellular complexes that are required for the successful metastasis of these and other malignancies.
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Affiliation(s)
- Kent W Hunter
- Laboratory of Population Genetics, CCR/NCI/NIH, 41 Library Drive, Bethesda, MD 20892-5060, USA.
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