OJGas  Vol.4 No.9 , September 2014
The Number of Ezrin-Expressing Lymphocytes Correlating with Tumor Cell Apoptosis and Prognosis of Human Gastric Carcinoma
ABSTRACT
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.

Cite this paper
Matsubara, T. , Hirahara, N. , Hyakudomi, R. and Tajima, Y. (2014) The Number of Ezrin-Expressing Lymphocytes Correlating with Tumor Cell Apoptosis and Prognosis of Human Gastric Carcinoma. Open Journal of Gastroenterology, 4, 310-320. doi: 10.4236/ojgas.2014.49045.
References
[1]   Parkin, D.M. (2001) Global Cancer Statistics in the Year 2000. The Lancet Oncology, 2, 533-543.
http://dx.doi.org/10.1016/S1470-2045(01)00486-7

[2]   Dhar, D.K., Kubota, H., Tachibana, M., Kinugasa, S., Masunaga, R., Shibakita, M., Kohno, H. and Nagasue, N. (2001) Prognosis of T4 Gastric Carcinoma Patients: An Appraisal of Aggressive Surgical Treatment. Journal of Surgical Oncology, 76, 278-282.
http://dx.doi.org/10.1002/jso.1046

[3]   Tsukita, S. and Yonemura, S. (1997) ERM (Ezrin/Radixin/Moesin) Family: From Cytoskeleton to Signal Transduction. Current Opinion in Cell Biology, 9, 70-75.
http://dx.doi.org/10.1016/S0955-0674(97)80154-8

[4]   Vaheri, A., Carpén, O., Heiska, L., Helander, T.S., Jaaskelainen, J., Majander-Nordenswan, P., Sainio, M., Timonen, T. and Turunen, O. (1997) The Ezrin Protein Family: Membrane-Cytoskeleton Interactions and Disease Associations. Current Opinion in Cell Biology, 9, 659-666.
http://dx.doi.org/10.1016/S0955-0674(97)80119-6

[5]   Yonemura, S., Hirao, M., Doi, Y., Takahashi, N., Kondo, T., Tsukita, S. and Tsukita, S. (1998) 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. The Journal of Cell Biology, 140, 885-895.
http://dx.doi.org/10.1083/jcb.140.4.885

[6]   Tsukita, S., Oishi, K., Sato, N., Sagara, J., Kawai, A. and Tsukita, S. (1994) ERM Family Members as Molecular Linkers between the Cell Surface Glycoprotein CD44 and Actin-Based Cytoskeletons. The Journal of Cell Biology, 126, 391-401.
http://dx.doi.org/10.1083/jcb.126.2.391

[7]   Heiska, L., Alfthan, K., Gronholm, M., Vilja, P., Vaheri, A. and Carpén, O. (1998) Association of Ezrin with Intercellular Adhesion Molecule-1 and -2 (ICAM-1 and ICAM-2). Regu-lation by Phosphatidylinositol 4,5-Bisphosphate. The Journal of Biological Chemistry, 273, 21893-21900.
http://dx.doi.org/10.1074/jbc.273.34.21893

[8]   Gautreau, A., Poullet, P., Louvard, D. and Arpin, M. (1999) Ezrin, a Plasma Membrane-Microfilament Linker, Signals Cell Survival through the Phosphatidylinositol 3-Kinase/Akt Pathway. Proceedings of the National Academy of Sciences of the United States of America, 96, 7300-7305.
http://dx.doi.org/10.1073/pnas.96.13.7300

[9]   Dransfield, D.T., Bradford, A.J., Smith, J., Martin, M., Roy, C., Mangeat, P.H. and Goldenring, J.R. (1997) Ezrin Is a Cyclic AMP-Dependent Protein Kinase Anchoring Protein. The EMBO Journal, 16, 35-43.
http://dx.doi.org/10.1093/emboj/16.1.35

[10]   Mackay, D.J., Esch, F., Furthmayr, H. and Hall, A. (1997) Rho- and Rac-Dependent Assembly of Focal Adhesion Complexes and Actin Filaments in Permeabilized Fibroblasts: An Essential Role for Ezrin/Radixin/Moesin Proteins. The Journal of Cell Biology, 138, 927-938.
http://dx.doi.org/10.1083/jcb.138.4.927

[11]   Berryman, M., Franck, Z. and Bretscher, A. (1993) Ezrin Is Concentrated in the Apical Microvilli of a Wide Variety of Epithelial Cells Whereas Moesin Is Found Primarily in Endothelial Cells. Journal of Cell Science, 105, 1025-1043.

[12]   Rosenberg, S.A. (1996) The Immunotherapy of Solid Cancers Based on Cloning the Genes Encoding Tumor-Rejection Antigens. Annual Review of Medicine, 47, 481-491.
http://dx.doi.org/10.1146/annurev.med.47.1.481

[13]   Thuillier, L., Hivroz, C., Fagard, R., Andreoli, C. and Mangeat, P. (1994) Ligation of CD4 Surface Antigen Induces Rapid Tyrosine Phosphorylation of the Cytoskeletal Protein Ezrin. Cellular Immunology, 156, 322-331.
http://dx.doi.org/10.1006/cimm.1994.1178

[14]   Roumier, A., Olivo-Marin, J.C., Arpin, M., Michel, F., Martin, M., Mangeat, P., Acuto, O., Dautry-Varsat, A. and Alcover, A. (2001) The Membrane-Microfilament Linker Ezrin Is Involved in the Formation of the Immunological Synapse and in T Cell Activation. Immunity, 15, 715-728.
http://dx.doi.org/10.1016/S1074-7613(01)00225-4

[15]   Moilanen, J., Lassus, H., Leminen, A., Vaheri, A., Bützow, R. and Carpén, O. (2003) Ezrin Immunoreactivity in Relation to Survival in Serous Ovarian Carcinoma Patients. Gynecologic Oncology, 90, 273-281.
http://dx.doi.org/10.1016/S0090-8258(03)00262-2

[16]   Hira, E., Ono, T., Dhar, D.K., El-Assal, O.N., Hishikawa, Y., Yamanoi, A. and Nagasue, N. (2005) Overexpression of Macrophage Migration Inhibitory Factor Induces Angio-genesis and Deteriorates Prognosis after Radical Resection for Hepatocellular Carcinoma. Cancer, 103, 588-598.
http://dx.doi.org/10.1002/cncr.20818

[17]   Lue, R.A., Brandin, E., Chan, E.P. and Branton, D. (1996) Two Inde-pendent Domains of hDlg Are Sufficient for Subcellular Targeting: The PDZ1-2 Conformational Unit and an Alterna-tively Spliced Domain. Journal of Cell Biology, 135, 1125-1137.
http://dx.doi.org/10.1083/jcb.135.4.1125

[18]   Trofatter, J.A., MacCollin, M.M., Rutter, J.L., Murrell, J.R., Duyao, M.P., Parry, D.M., Eldridge, R., Kley, N., Menon, A.G., Pulaski, K., et al. (1993) A Novel Moesin-, Ezrin-, Radixin-Like Gene Is a Candidate for the Neurofibromatosis 2 Tumor Suppressor. Cell, 72, 791-800.
http://dx.doi.org/10.1016/0092-8674(93)90406-G

[19]   Tran, Y.K., Bogler, O., Gorse, K.M., Wieland, I., Green, M.R. and Newsham, I.F. (1999) A Novel Member of the NF2/ERM/4.1 Superfamily with Growth Suppressing Properties in Lung Cancer. Cancer Research, 59, 35-43.

[20]   Pang, S.T., Fang, X., Valdman, A., Norstedt, G., Pousette, A., Egevad, L. and Ekman, P. (2004) Expression of Ezrin in Prostatic Intraepithelial Neoplasia. Urology, 63, 609-612.
http://dx.doi.org/10.1016/j.urology.2003.09.068

[21]   Helander, T.S., Carpén, O., Turunen, O., Kovanen, P.E., Vaheri, A. and Timonen, T. (1996) ICAM-2 Redistributed by Ezrin as a Target for Killer Cells. Nature, 382, 265-268.
http://dx.doi.org/10.1038/382265a0

[22]   Shen, Z.Y., Xu, L.Y., Li, E.M., Li, J.T., Chen, M.H., Shen, J. and Zeng, Y. (2003) Ezrin, Actin and Cytoskeleton in Apoptosis of Esophageal Epithelial Cells Induced by Arsenic Trioxide. International Journal of Molecular Medicine, 12, 341-347.

[23]   Kondo, T., Takeuchi, K., Doi, Y., Yonemura, S., Nagata, S. and Tsukita, S. (1997) ERM (Ezrin/Radixin/Moesin)-Based Molecular Mechanism of Microvillar Breakdown at an Early Stage of Apoptosis. Journal of Cell Biology, 139, 749-758.
http://dx.doi.org/10.1083/jcb.139.3.749

[24]   Ramoni, C., Luciani, F., Spadaro, F., Lugini, L., Lozupone, F. and Fais, S. (2002) Differential Expression and Distribution of Ezrin, Radixin and Moesin in Human Natural Killer Cells. European Journal of Immunology, 32, 3059-3065.
http://dx.doi.org/10.1002/1521-4141(200211)32:11<3059::AID-IMMU3059>3.0.CO;2-3

[25]   Oka, M., Yoshino, S., Hazama, S., Shimoda, K., Suzuki, M. and Suzuki, T. (1992) Prognostic Significance of Regional Lymph Node Re-action after Curative Resection of Advanced Gastric Cancer. British Journal of Surgery, 79, 1091-1094.
http://dx.doi.org/10.1002/bjs.1800791034

[26]   Di Giorgio, A., Botti, C., Mingazzini, P., Canavese, A. and Arnone, P. (1995) Gastric Cancer: Prognosis and Lymph Node Reactivity. European Journal of Surgery, 161, 575-580.

[27]   Maehara, Y., Tomisaki, S., Oda, S., Kakeji, Y., Tsujitani, S., Ichiyoshi, Y., Akazawa, K. and Sugimachi, K. (1997) Lymph Node Metastasis and Relation to Tumor Growth Potential and Local Immune Response in Advanced Gastric Cancer. International Journal of Cancer, 74, 224-228.
http://dx.doi.org/10.1002/(SICI)1097-0215(19970422)74:2<224::AID-IJC15>3.0.CO;2-D

[28]   Elliott, B.E., Meens, J.A., SenGupta, S.K., Louvard, D. and Arpin, M. (2005) The Membrane Cytoskeletal Crosslinker Ezrin Is Required for Metastasis of Breast Carcinoma Cells. Breast Cancer Research, 7, R365-R373.
http://dx.doi.org/10.1186/bcr1006

 
 
Top