Role of TGF-β1-independent changes in protein neosynthesis, p38αMAPK, and cdc42 in hydrogen peroxide-induced senescence-like morphogenesis
Aline ChrétienJean‐François DierickEdouard DelaiveMartin R. LarsenMarc DieuMartine RaesChristophe DeroannePeter RoepstorffOlivier Toussaint
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Keywords:
CDC42
Hsp27
Senescence
Background: Ezrin is a linker protein between actin filaments and cell adhesion molecules, which plays an important role in cancer progression. There are only a few studies available that have investigated ezrin expression in different types of tumors. However, the prognostic importance of ezrin and its correlation with clinicopathological characteristics are yet to be delineated in gastric carcinoma. Methods: Specimens from 124 gastric carcinoma patients of T2 and T3 diseases treated in a defined period with curative operation were evaluated for ezrin, CD8 and cleaved caspase-3 expression by immunohistochemical methods. Results: Ezrin expression was detected in both cancer cells and interstitial cells (ISCs) infiltrated into the tumor. According to our criterion, 37 patients (29.8%) were positive for ezrin expression and 87 (70.2%) were negative. A significant correlation between ezrin expression and any of the clinicopathological characteristics could not be found. In Spearman-rank correlation test, a significant correlation was found between the number of ezrin-stained ISCs and apoptotic index (AI) of cancer cells. Also the AI of cancer cells was significantly higher in ezrin-positive group when compared with ezrin-negative group. Patients with ezrin-expressing tumors had a significantly better disease-free survival, and in multivariable analysis ezrin expression status remained significant as an independent prognostic factor. Conclusion: Taken together, our results suggest that ezrin expression may play a vital role in tumor apoptosis and that it can be a useful tool for therapeutic intervention.
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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.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.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).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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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). 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. 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. Ezrin and p-ezrin, especially ezrinThr-567, may prove to be useful as a novel prognostic biomarker of NSCLC.
Surgical oncology
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Moesin
Radixin
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Establishment of polarized cell morphology is a critical factor for migration and requires precise spatial and temporal activation of the Rho GTPases. Here, we describe a novel role of the actin-binding ezrin/radixin/moesin (ERM)-protein ezrin to be involved in recruiting Cdc42, but not Rac1, to lipid raft microdomains, as well as the subsequent activation of this Rho GTPase and the downstream effector p21-activated kinase (PAK)1, as shown by fluorescence lifetime imaging microscopy. The establishment of a leading plasma membrane and the polarized morphology necessary for random migration are also dependent on ERM function and Cdc42 in motile breast carcinoma cells. Mechanistically, we show that the recruitment of the ERM-interacting Rho/Cdc42-specific guanine nucleotide exchange factor Dbl to the plasma membrane and to lipid raft microdomains requires the phosphorylated, active conformer of ezrin, which serves to tether the plasma membrane or its subdomains to the cytoskeleton. Together these data suggest a mechanism whereby precise spatial guanine nucleotide exchange of Cdc42 by Dbl is dependent on functional ERM proteins and is important for directional cell migration.
CDC42
Radixin
Moesin
Lipid raft
PAK1
Small GTPase
Rac GTP-Binding Proteins
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Abstract It is generally recognized that osteoporosis is a common complication of patients with glucocorticoid excess and that glucocorticoid receptor is associated with heat shock protein (HSP) 70 and HSP90 in a heterocomplex. In the present study, we investigated whether glucocorticoid induces HSP27, HSP70, and HSP90 in osteoblast‐like MC3T3‐E1 cells. Dexamethasone time‐dependently increased the levels of HSP27, while having no effect on the levels of HSP70 or HSP90. The effect of dexamethasone was dose‐dependent in the range between 0.1 nM and 0.1 μM. Dexamethasone induced an increase of the levels of mRNA for HSP27. Dexamethasone induced the phosphorylation of p38 mitogen‐activated protein (MAP) kinase. SB203580 and PD169316, inhibitors of p38 MAP kinase, suppressed the HSP27 accumulation by dexamethasone. In addition, SB203580 reduced the dexamethasone‐stimulated increase of the mRNA levels for HSP27. The dexamethasone‐induced phosphorylation of p38 MAP kinase was reduced by SB203580. These results strongly suggest that glucocorticoid stimulates the induction of neither HSP70 nor HSP90, but HSP27 in osteoblasts, and that p38 MAP kinase is involved in the induction of HSP27. © 2002 Wiley‐Liss, Inc.
Hsp27
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