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Clinical Cancer Research Vol. 10, 572-580, January 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Clinical Significance of Cellular Distribution of Moesin in Patients with Oral Squamous Cell Carcinoma

Hiroichi Kobayashi1, Junji Sagara2, Hiroshi Kurita1, Masayo Morifuji3, Masamichi Ohishi3, Kenji Kurashina1 and Shun’ichiro Taniguchi2

1 Departments of Dentistry and Oral Surgery and 2 Molecular Oncology and Angiology, Aging and Adaptation, Shinshu University School of Medicine, Matsumoto, Japan and 3 First Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Kyushu University, Fukuoka, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Moesin is a linking protein of the submembraneous cytoskeleton and plays a key role in the control of cell morphology, adhesion, and motility. The aim of the present study was to elucidate the clinical significance of expression patterns of moesin in patients with oral squamous cell carcinoma (OSCC).

Experimental Design: Immunohistochemistry for moesin monoclonal antibody was performed on 103 paraffin-embedded specimens from patients with primary OSCC, including 30 patients with locoregional lymph node metastasis, and in the sections from nude mice transplanted with two cell lines derived from a single human tongue cancer (SQUU-A and SQUU-B).

Results: Expression patterns of moesin in OSCCs were divided into three groups: membranous pattern; mixed pattern; and cytoplasmic pattern. These expression patterns correlated with tumor size, lymph node metastasis, mode of invasion, differentiation, and lymphocytic infiltration. In about two-thirds of the patients with metastatic lymph node, homogeneous cytoplasmic expression was detected in the metastatic lymph nodes. In addition, SQUU-B with high metastatic potential showed more reduced levels of membrane-bound moesin than SQUU-A with low metastatic potential. A multivariate analysis demonstrated that expression patterns of moesin can be an independent prognostic factor.

Conclusions: Our results suggest that moesin expression contributed to discriminating between patients with the potentiality for locoregional lymph node metastasis and those with a better prognosis and might improve the definition of suitable therapy for each.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Oral cancer, 1 of the 10 most common cancers in the world, remains a morbid and often fatal disease. Despite marked advances of management and diagnosis of oral squamous cell carcinoma (OSCC), the overall survival ratio has showed only a modest increase in recent years. Therefore, the development of molecular markers is needed to improve the diagnosis and assessment of tumor progression and metastasis in OSCC patients.

Moesin is a member of the ERM (ezrin/radixin/moesin) family, which shares ~78% amino acid sequence identity with each other. ERM proteins, part of the band 4.1 superfamily, act as a membrane-cytoskeleton linker in actin-enriched specialized plasma membrane structures, especially microvilli, ruffling membranes, and cleavage furrows and thus play a key role in the control of cell morphology, adhesion, and motility (1, 2, 3, 4, 5, 6) . The integral membrane proteins such as CD44, CD43, intercellular adhesion molecules 1 and 2, and actin are identified as ligands for ERM proteins (7, 8, 9) . Merlin, encoded by the neurofibromatosis type 2, is classified as a tumor suppressor protein (10) . Because moesin shares high homology with Merlin and colocalizes with it beneath the plasma membrane, it has been speculated that moesin may also be a tumor suppressor (11 , 12) . However, recent studies have indicated that ERM proteins are up-regulated in various kinds of tumors (13, 14, 15, 16, 17) . Whether moesin is functional as a tumor suppressor in carcinogenesis and tumor development remains unclear.

Because little is known about the role of moesin in the oral normal mucosa and oral lesions, including leukoplakia, verrucous carcinoma, and small cell carcinoma, we initiated a series of studies aimed at characterizing expression of moesin (18) . In this particular study, we report that OSCC cells constitutively display several expression patterns of moesin, thereby providing a new biomolecular marker for use in prediction of metastasis and poor prognosis.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tumor Sample.
The study group consisted of 103 patients with OSCC who were diagnosed at the Department of Dentistry and Oral Surgery, Shinshu University School of Medicine. Tissues of primary (n = 103) and metastatic (n = 30) lesions of OSCCs were collected during biopsy or operation after patients signed the informed consent form approved by the Institution Review Committee. Permission to perform this study was obtained from the committee. Thirty-one patients (T1–T2) without lymph node metastasis underwent radiotherapy alone while 72 patients underwent surgery. The grade of tumor differentiation was determined according to the criteria proposed by the WHO (19) . Mode of invasion was classified according to Jakobsson’s classification (20) . Median follow-up time was 32.0 months (range, 2–115 months). The study population consisted of 59 men and 44 women averaging 65.0 years of age (range, 27–88 years). For controls, normal oral mucosa were obtained from consenting patients during removal of a lower wisdom tooth.

Cell Lines and Culture.
Human oral cancer cell lines, SQUU-A and SQUU-B, were established as reported previously (21) . These cell lines were cultured in Eagle’s MEM (Nissui, Tokyo, Japan) supplemented with 10% fetal bovine serum (Life Technologies, Inc., Grand Island, NY), penicillin (100 IU/ml), streptomycin (100 mg/ml), and fungizone (1 mg/ml) at 37°C in an atmosphere of 5% CO2.

Animals and Experimental Treatment.
Female BALB/c mice (6 weeks old) were purchased from SLC (Shizuoka, Japan) and were housed under conventional conditions with free access to animal chow and water. Under general anesthesia with diethylether, ~3.5 x 105/0.035 ml viable cells were injected in the s.c. tissue of the right side of the tongue. The mice were sacrificed 5 weeks after the infection, and tongues were resected. The care and use of these experimental animals were in accordance with institutional guidelines.

Antibodies and Immunohistochemical Staining.
Mouse monoclonal antibody (CR-22) was kindly provided by Drs. Shoichiro Tsukita and Sachiko Tsukita, Kyoto University (Kyoto, Japan); this antibody has a higher affinity for moesin (22) . The specificity of antibody against moesin was confirmed with Western blotting and immunoprecipitation of the cell lysates from human peripheral leukocyte (23) and human malignant melanoma cells (11) . In addition, the samples were reported to show similar staining in frozen sections as well as formalin-fixed, paraffin-embedded section (11 , 23) . Furthermore, our previous study also validated the specificity of this antigen by Western blot analysis from OSCC tissues and immunohistochemical staining in frozen OSCC tissues (18) . Horseradish peroxidase-conjugated goat antimouse polyclonal antibody (Dako, Copenhagen, Denmark) and anti-actin (ß) monoclonal antibody (Abcam, Cambridge, United Kingdom) were purchased, respectively.

All samples were fixed in 10% formalin and embedded in paraffin to prepare serial sections. Expression of moesin was examined by the indirect peroxidase technique as described previously (23) . Tissues embedded in paraffin were cut into 3-µm sections and mounted onto silane-coated glass slides. The slides were dewaxed in xylene, dehydrated in descending dilutions of ethanol, and preincubated with a solution of 1% hydrogen peroxide in methanol to suppress the endogenous peroxidase for 30 min at room temperature. After being rinsed in distilled water, the sections were microwaved (500 w, 25 min) for antigen retrieval in 0.01 M citric acid (pH 6.0). After being washed with distilled water and 0.05 M Tris-buffered saline (TBS; pH 7.6), the specimens were treated with mouse anti-moesin antibody diluted by TBS containing 1% BSA at 4°C overnight, washed three times with TBS, and then incubated with goat antimouse immunoglobulin polyclonal antibody diluted by TBS containing 1% BSA for 60 min at room temperature. After being washed three times with TBS, the sections were developed in 0.05 M Tris-buffer (pH 7.6) containing 25 mg/125 ml 3,3'-diaminobenzidine and 0.0015% hydrogen peroxide for 7 min. The sections were then washed in water, counterstained with Mayer’s hematoxylin, dehydrated, cleaned, and coverslipped. Negative controls were treated by replacing the primary antibody with TBS 1% BSA.

Scoring of Results.
Sections were examined by two independent researchers (H. Ko., H. Ku.) in an effort to provide a consensus of staining pattern. Moesin or ß-actin expression of neoplastic cell in primary lesions was classified as follows: membranous pattern—membranous expression of moesin or ß-actin was more dominant than cytoplasmic expression; mixed pattern—membranous expression of moesin or ß-actin was approximately equal to cytoplasmic expression; and cytoplasmic pattern—membranous expression of moesin or ß-actin was weaker than cytoplasmic expression. We used the expression pattern of moesin used as the predominant pattern on the whole histological section of the tumor.

Thirty cases with locoregional lymph node metastasis were evaluated for heterogeneity of tumor cells in the primary lesions as well as in the metastatic lesions by examination in 10 randomized fields of sections at a magnification of x400. Expression percentages of cytoplasmic expression pattern of moesin was calculated from these.

Statistics.
The relationships between expression of moesin and clinicopathological indices such as age, gender, tumor size, lymph node metastasis, differentiation, mode of invasion, and lymphocytic infiltration were evaluated by Mann-Whitney’s U test. Kaplan-Meier survival curves were constructed and log-rank tests performed to assess whether the expression pattern of moesin in neoplastic cells had any effect on overall survival of patients with oral cancer. Relative risk of death was calculated by univariate and multivariate analysis using Cox regression models. The correlation between expression patterns of moesin and ß-actin was estimated by Spearman’s rank correlation.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Moesin Expression in Normal Oral Epithelia.
In basal layer cells as well as restricted parabasal layer cells and spinous layer cells, the membranous expression pattern of moesin is dominant. Weak immunoreactivity for moesin was seen in the cytoplasm of basal layer cells, and no apparent staining with anti-moesin antibody was observed in cornified layer cells (Fig. 1, A and B)Citation .



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  		Fig. 1. Staining of normal oral epithelium with monoclonal antibody against moesin. A, expression level was gradually reduced from the parabasal layer toward the top layer. B, reactivity for moesin monoclonal antibody was prominent in the cell membrane of basal layer and parabasal layer cells. Bar, 100 µm in A; 10 µm in B.

 
Moesin Expression in Primary and Metastatic Tumors.
In a previous study, we showed that moesin expression decreased in the membrane and increased in the cytoplasm in accordance with the degree of transformation and malignancy of oral lesions, including OSCC, verrucous carcinoma, and dysplastic lesion. In this study, we focused on moesin expression in primary tumors and metastatic lymph nodes.

The cellular distribution pattern of moesin differed substantially in primary tumors and metastatic lymph nodes. We divided moesin distribution patterns into three types: membranous (Fig. 2A)Citation ; mixed (Fig. 2B)Citation ; and cytoplasmic (Fig. 2C)Citation patterns. In OSCC patients with locoregional lymph node metastasis, primary tumors showed various distribution patterns of moesin as in Fig. 2Citation , but most metastatic tumors in lymph nodes showed the cytoplasmic distribution pattern. A case of OSCC patient with cervical lymph node metastasis is presented in Fig. 3Citation . Membranous or cytoplasmic patterns are seen in the primary tumor of the patient (Fig. 3, A–D)Citation , but all of the metastatic tumors in the lymph nodes display the cytoplasmic pattern (Fig. 3, E and F)Citation . Comparison in moesin expression between primary and metastatic tumors in the same patients demonstrated that metastatic cells predominantly showed cytoplasmic pattern, whereas primary tumors showed heterogeneous expression patterns (Fig. 4)Citation .



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  		Fig. 2. Three staining patterns in oral squamous cell carcinomas with monoclonal antibody against moesin. A, membranous expression pattern, predominant expression in the cell membrane. B, mixed expression pattern, reactivity in the cell membrane about equal to that in the cytoplasm. C, cytoplasmic expression pattern, predominant cytoplasmic labeling. Bar, 10 µm.

 


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  		Fig. 3. Immunohistochemical localization of moesin in primary tissue and metastatic lymph nodes of the same oral squamous cell carcinoma patient. A and B, membranous expression of moesin in primary tissue. C and D, cytoplasmic expression in front of an invasive margin of primary tumor cells. E and F, cytoplasmic expression homogeneously observed. Bar, 100 µm in A, C, and E; 10 µm in B, D, and F.

 


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  		Fig. 4. Comparison of percentage of cytoplasmic expression of moesin in primary tissues and metastatic lymph nodes in the same oral squamous cell carcinoma patient with cervical lymph node metastasis. In all primary tissues, cytoplasmic expression type was heterogeneously observed (range, 10–92%), whereas in about two-thirds of the metastatic lymph nodes, cytoplasmic expression pattern was homogeneously displayed.

 
Relationships between Expression Pattern of Moesin and Clinicopathological Parameters and Prognosis in OSCC Patients.
We compared moesin expression pattern with clinicopathological parameters in 103 OSCC patients (Table 1)Citation . There was an association of expression pattern of moesin with tumor size, cervical lymph node involvement, mode of invasion, differentiation, and lymphocytic infiltration. However, the expression pattern of moesin did not differ significantly with respect to age and gender.


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  		Table 1 Expression pattern of moesin in oral squamous cell carcinoma according to clinicopathological features of patients

 
By the Kaplan-Meier curves, there was significant difference among three groups, membranous pattern, mixed pattern, and cytoplasmic pattern ({chi}2 = 18.841, P < 0.0001 by log-rank test; Fig. 5Citation ).



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  		Fig. 5. Kaplan-Meier survival curves of patients with oral squamous cell carcinoma according to expression pattern of moesin. The survival curves were analyzed by the log-rank test.

 
Univariate regression analysis showed that overall survival correlated with tumor size, cervical lymph node metastasis, mode of invasion, differentiation, lymphocytic infiltration, and expression pattern of moesin. Furthermore, a multivariate analysis using the Cox proportional hazards model also showed that the expression pattern of moesin (P = 0.0470) is significantly associated with overall survival (Table 2)Citation .


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  		Table 2 Univariate and multivariate analysis of clinicopathological data and expression pattern of moesin in 103 cases of oral cancer

 
Moesin Level and Cellular Localization in Oral Cancers.
In the next experiments, we investigated the expression of moesin in established cell lines of OSCC. Mixed or predominantly cytoplasmic expression patterns of moesin were detected in a large number of SQUU-A cells with low metastatic potential. These cells showed predominantly membranous expression of moesin in some part (Fig. 6, A and B)Citation , whereas the whole of SQUU-B cells with high metastatic activity exhibited a down-regulation of membranous expression and an increase in cytoplasmic expression (Fig. 6, C and D)Citation .



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  		Fig. 6. Moesin localization in sections from nude mice transplanted with two cell lines. Tumor cell, at least in part, showed membranous expression of moesin in SQUU-A with low metastatic ability (A and B), but not in the SQUU-B with high metastatic ability (C and D). Bar, 50 µm in A and C; 10 µm in B and D.

 
Correlation between Expression Patterns of Moesin and ß-Actin in Primary Tumors.
In normal oral epithelia, basal layer and parabasal layer cells showed homogeneous cytoplasmic staining against anti-actin (ß) monoclonal antibody and spinous layer cells showed juxtamembranous staining toward the top layer (Fig. 7A)Citation . Moreover, in the cytoplasm of all of the tumor cells, ß-actin was stained. Especially, in well differentiated tumor cells without lymph node metastasis, ß-actin was strongly stained beneath the cell membrane (Fig. 7B)Citation , whereas ß-actin was homogeneously observed in poorly differentiated tumor cells with lymph node metastasis (Fig. 7C)Citation . Twenty-six (92.8%) of 28 patients whose tumors showed membranous expression pattern of moesin showed membranous expression of ß-actin, and 31 (83.8%) of 37 patients whose tumors showed cytoplasmic expression pattern of moesin showed mixed expression pattern of ß-actin. However, no patients showed cytoplasmic expression pattern of ß-actin. Significant correlation between expression patterns of moesin and ß-actin was observed (P < 0.0001; Table 3Citation ).



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  		Fig. 7. Distribution of ß-actin in normal oral epithelia and primary oral squamous cell carcinoma tissues. A, normal oral epithelia. B, well-differentiated carcinoma tissue without lymph node metastasis. C, poorly differentiated carcinoma tissue with lymph node metastasis. Bar, 25 µm.

 

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  		Table 3 Correlation between expression patterns of moesin and ß-actin in primary oral squamous cell carcinomaa

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we noted that expression pattern of moesin correlated with tumor size, cervical lymph node metastasis, mode of invasion, differentiation, and lymphocytic infiltration. Furthermore, our results demonstrated that tumor cells with cytoplasmic expression of moesin showed higher incidence of lymph node metastasis than tumor cells with membranous expression of moesin. This is consistent with the observation that using a murine model in which almost all the whole cells in a highly metastatic cell line (SQUU-B) showed cytoplasmic expression of moesin, whereas a small number of cells in a less metastatic cell line (SQUU-A) showed membranous expression. Although the biological significance of cellular translocation of moesin is unclear, there are several explanations for these findings. Firstly, conformational and functional change of moesin results in redistribution of this molecule in tumor cells. Inactive moesin is self-associated between the COOH-terminal domain and NH2-terminal domain existing in the cytoplasm (24) . Upon receipt of appropriate activators, phosphatidylinositol 4,5-bisphosphate (25) or phosphorylation of Thr558 (26) , moesin translocates from the cytoplasm to the juxtamembrane by disruption of its intramolecular binding. Thus, the change of balance of activator and/or inactivator for moesin may bring about cellular translocation of the molecule. It has been suggested that phosphatidylinositol 4,5-bisphosphate production is activated by oncogenic Ras through phosphatidylinositol 3-kinase and G protein Rac-induced malignant transformation (27) . Secondly, CD44, a cell surface receptor involved in cell adhesion, tumor invasion, and metastasis, has been cleaved by membrane-type 1 matrix metalloproteinase in carcinoma cells at a membrane-proximal domain, thereby suggesting that functional moesin migrates with CD44 degraded from the cell surface to the cytoplasm (28) . Thirdly, because significant correlation between expressions pattern of moesin and ß-actin was observed in primary carcinoma tissues, change of moesin distribution in tumor cells may reflect organization of the actin cytoskeleton and an altered cellular environment. Fourthly, according to carcinogenesis, it is possible that mutant of moesin cannot cross-link between plasma membrane and actin filament, which shows an increase in the cytoplasm of neoplastic cells.

Of interest, our previous studies found that OSCC displayed higher rate of cytoplasmic expression pattern when compared with the pattern in normal oral epithelium, oral epithelial dysplasia, and verrucous carcinoma (18) . Furthermore, it has been reported that squamous cell carcinoma in the skin showed cytoplasmic expression of moesin (29) . However, another study demonstrated that membranous labeling of ezrin was highly observed in metastatic tissues as compared with the primary tissues or hyperplastic specimens (30) . A recent study indicated that ezrin and moesin might be regulated differently because the binding activity of ezrin and moesin to L-selectin differed when phorbol myristate acetate stimulation and protein kinase C inhibitor were used (31) . Thus, the discrepancy between the study and our series may suggest different regulation among ERM proteins and a distinct role for moesin, depending on the type of cancer.

Interestingly, all specimens in the primary tumors revealed heterogeneous expression pattern of moesin, but most specimens in the metastatic lymph nodes homogeneously showed cytoplasmic expression of moesin. We detected cytoplasmic expression of moesin in the marginal carcinoma cells of the nests, which seem to constitute the advancing front of cancer invasion. We speculate that because carcinoma cells at the invasive front in primary tumors show cytoplasmic expression of moesin, which greatly degrade the extracellular matrix as well as CD44, these cells probably are involved in pathological processes of tumor invasion and metastasis.

The tumor size and regional lymph node involvement are known as indicators for tumor aggressiveness and poor outcome in OSCC patients. In this study, we observed the same association using univariate analysis. Furthermore, our data indicated that expression pattern of moesin has a prognostic value: patients whose tumors showed cytoplasmic expression had a poorer overall survival compared with patients whose tumors showed cell membranous expression. In this study, multivariate analysis demonstrated dramatically that the expression pattern of moesin is the only independent prognostic factor in patients with OSCC. In view of its clinical usefulness, early detection methods clearly predict locoregional lymph node metastasis as well as poor clinical outcome may improve strategic planning. We therefore recommend assessing the expression pattern of moesin using pretreatment specimens in OSCC clinical trials in an effort to validate the most appropriate treatments.

This is the first study to state that the expression pattern of moesin is an independent prognostic indicator for patients with OSCC. The expression pattern of moesin may be a clinically useful marker for selection of patients for specific treatments; moreover, modulation of the expression pattern of moesin is a potential therapeutic strategy for improving clinical outcome in OSCC patients.


   ACKNOWLEDGMENTS
 
We thank Drs. Shoichiro Tsukita and Sachiko Tsukita for their kind gift of anti-moesin monoclonal antibody (CR-22).


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Hiroichi Kobayashi, Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. Phone: 81-263-37-2677; Fax: 81-263-37-2676; E-mail: h-koba{at}hsp.md.shinshu-u.ac.jp

Received 11/ 1/02; revised 10/14/03; accepted 10/20/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Algrain M., Turunen O., Vaheri A., Louvard D., Arpin M. Ezrin contains cytoskeleton and membrane-binding domains accounting for its proposed role as a membrane-cytoskeletal linker. J. Cell Biol., 120: 129-139, 1993.[Abstract/Free Full Text]
  2. Vaheri A., Carpen O., Heiska L., Halender T. S., Jaaskelainen J., Majander-Nordenswan P., Sainio M., Timonen T., Turunen O. The ezrin protein family: membrane-cytoskeleton interactions and disease association. Curr. Opin. Cell Biol., 9: 659-666, 1997.[CrossRef][Medline]
  3. Crepaldi T., Gautreau A., Comglio P., Louvard D., Arpin M. Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells. J. Cell Biol., 138: 423-434, 1997.[Abstract/Free Full Text]
  4. Bretscher A. Regulation of cortical structure by the ezrin-radixin-moesin protein family. Curr. Opin. Cell Biol., 11: 109-116, 1999.[CrossRef][Medline]
  5. Tsukita S., Yonemura S. ERM (ezrin/radixin/moesin) family: From cytoskeleton to signal transduction. Curr. Opin. Cell Biol., 9: 70-75, 1997.[CrossRef][Medline]
  6. Tsukita S., Yonemura S. Cortical actin organization: Lessons from ERM (ezrin/radixin/moesin) proteins. J. Biol. Chem., 274: 34507-34510, 1999.[Free Full Text]
  7. Tsukita Sa., Oishi K., Sato N., Sagara J., Kawai A., Tsukita Sh. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J. Cell Biol., 126: 391-401, 1994.[Abstract/Free Full Text]
  8. Yonemura S., Hirao M., Doi Y., Takahashi N., Kondo T., Tsukita Sa., Tsukita Sh. Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. J. Cell Biol., 140: 885-895, 1998.[Abstract/Free Full Text]
  9. Heiska L., Alfthan K., Gronholm M., Vilja P., Vaheri A., Carpen O. Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). J. Biol. Chem., 273: 21893-21900, 1998.[Abstract/Free Full Text]
  10. Martuza R. L., Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N. Engl. J. Med., 318: 684-688, 1988.[Medline]
  11. Ichikawa T., Masumoto J., Kaneko M., Saida T., Sagara J., Taniguchi S. Moesin and CD44 expression in cutaneous melanocytic tumours. Br. J. Dermatol., 138: 763-768, 1998.[CrossRef][Medline]
  12. Tokunou M., Niki T., Saitoh Y., Imamura H., Sakamoto M., Hirohashi S. Altered expression of the ERM proteins in lung adenocarcinoma. Lab. Investig., 80: 1643-1650, 2000.[Medline]
  13. Bohling T., Turunen O., Jaaskelainen J., Carpen O., Sainio M., Wahlstrom T., Vaheri A., Haltia M. Ezrin expression in stromal cells of capillary hemangioblastoma. An immunohistochemical survey of brain tumors. Am. J. Pathol., 148: 367-373, 1996.[Abstract]
  14. Fazioli F., Wong W. T., Ullrich S. J., Sakaguchi K., Appella E., Di Fiore P. P. The ezrin-like family of tyrosine kinase substrates: receptor-specific pattern of tyrosine phosphorylation and relationship to malignant transformation. Oncogene, 8: 1335-1345, 1993.[Medline]
  15. Kaul S. C., Mitsui Y., Komatsu Y., Reddel R. R., Wadhwa R. A highly expressed 81-kDa protein in immortalized mouse fibroblast: its proliferative function and identity with ezrin. Oncogene, 13: 1231-1237, 1996.[Medline]
  16. Ohtani K., Sakamoto H., Rutherford T., Chen Z., Satoh K., Naftolin F. Ezrin, a membrane-cytoskeletal linking protein, is involved in the process of invasion of endometrial cancer cells. Cancer Lett., 147: 31-38, 1999.[CrossRef][Medline]
  17. Akisawa N., Nishimori I., Iwamura T., Onishi S., Hollingsworth M. A. High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential. Biochem. Biophys. Res. Commun., 258: 395-400, 1999.[CrossRef][Medline]
  18. Kobayashi H., Sagara J., Masumoto J., Kurita H., Kurashira K., Taniguchi S. Shift in cellular localization of moesin in normal oral epithelium, oral epithelial dysplasia, verrucous carcinoma and oral sqaumous cell carcinoma. J. Oral Pathol. Med., 32: 344-349, 2003.[Medline]
  19. Pindborg J. J., Reichert P. A., Smith C. J., van der Waal I. . World Health Organization International Histological Classification of Tumours: Histological Typing of Cancer and Precancer of the Oral Mucosa, Springer Publ. Berlin 1971.
  20. Jakobsson P. A., Eneroth C. M., Killander D., Moberger G., Martensson B. Histologic classification and grading of malignancy in carcinoma of the larynx. Acta Radiol. Ther. Phys. Biol., 12: 1-8, 1973.[Medline]
  21. Morifuji M., Taniguchi S., Sakai H., Nakabeppu Y., Ohishi M. Differential expression of cytokeratin after orthotopic implantation of newly established human tongue cancer cell lines of defined metastatic ability. Am. J. Pathol., 156: 1317-1325, 2000.[Abstract/Free Full Text]
  22. Sato N., Yonemura S., Obinata T., Tsukita Sa., Tsukita Sh. Radixin, a barbed end-capping actin-modulating protein, is concentrated at the cleavage furrow during cytokinesis. J. Cell Biol., 113: 321-330, 1991.[Abstract/Free Full Text]
  23. Masumoto J., Sagara J., Hayama M., Hidaka E., Katsuyama T., Taniguchi S. Differential expression of moesin in cells of hematopoietic lineage and lymphatic systems. Histochem. Cell Biol., 110: 33-41, 1998.[CrossRef][Medline]
  24. Gray R., Bretscher A. Ezrin self-association involves binding of an N-terminal domain to a normally masked C-terminal domain that includes the F-actin binding site. Mol. Biol. Cell, 6: 1061-1075, 1995.[Abstract]
  25. Matsui T., Maeda M., Doi Y., Yonemura S., Amano M., Kaibuchi K., Tsukita, Tsukita Sa., Tsukita Sh. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-tail association. J. Cell Biol., 140: 647-657, 1998.[Abstract/Free Full Text]
  26. Matsui T., Yonemura S., Tsukita S., Tsukita S. Activation of ERM proteins in vivo by Rho involves phosphatidyl-inositol 4-phosphate 5-kinase and not ROCK kinases. Curr. Biol., 9: 1259-1262, 1999.[CrossRef][Medline]
  27. Takenawa T., Itoh T., Fukami K. Regulation of phosphatidylinositol 4,5-biphosphate levels and its roles in cytoskeletal re-organization and malignant transformation. Chem. Phys. Lipids, 98: 13-22, 1999.[CrossRef][Medline]
  28. Kajita M., Itoh Y., Chiba T., Mori H., Okada A., Kinoh H., Seiki M. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J. Cell Biol., 153: 893-904, 2001.[Abstract/Free Full Text]
  29. Ichikawa T., Masumoto J., Kanoko M., Saida T., Sagara J., Taniguchi J. Expression of moesin and its associated molecule CD44 in epithelial skin tumors. J. Cutan. Pathol., 25: 237-243, 1998.[Medline]
  30. Ohtani K., Sakamoto H., Rutherford T., Chen Z., Kikuchi A., Yamamoto T., Satoh K., Naftolin F. Ezrin, a membrane-cytoskeletal linking protein, is highly expressed in atypical endometrial hyperplasia and uterine endometrioid adenocarcinoma. Cancer Lett., 179: 79-86, 2002.[CrossRef][Medline]
  31. Ivetic A., Deka J., Ridley A., Ager A. The cytoplasmic tail of L-selectin interacts with members of the ezrin-radixin-moesin (ERM) family of proteins. J. Biol. Chem., 277: 2321-2329, 2002.[Abstract/Free Full Text]



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