Abstract
Members of the 4.1 superfamily of proteins, including ezrin, moesin, merlin, and willin regulate many normal physiologic processes such as cellular shape, motility, and proliferation. In addition, they contribute both to tumor development and tumor progression. We reported previously that strong cytoplasmic ezrin expression was independently associated with poorer patient survival. One hundred and thirty-one histologically confirmed primary head and neck squamous cell carcinomas were examined prospectively for cancer progression and survival at a large health care center in the Bronx, NY, USA. Immunohistochemical analysis of ezrin, moesin, merlin, and willin expression in tissue microarray samples of primary head and neck squamous cell carcinoma revealed a significant association of increased cytoplasmic ezrin with poor cancer survival. Global RNA analyses suggest that cancers with high cytoplasmic ezrin have a more invasive phenotype. This study supports our previous findings associating cytoplasmic ezrin with more aggressive behavior and poorer outcome and indicates the need for a multi-institutional study to validate the use of cytoplasmic ezrin as a biomarker for treatment planning in head and neck squamous cell carcinoma.
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Belbin TJ, Singh B, Smith RV, et al. Molecular profiling of tumor progression in head and neck cancer. Arch Otolaryngol Head Neck Surg. 2005;131:10–8.
Fehon RG, McClatchey AI, Bretscher A. Organizing the cell cortex: the role of ERM proteins. Natl Rev Mol Cell Biol. 2010;11:276–87.
Sudol M, Harvey KF. Modularity in the Hippo signaling pathway. Trends Biochem Sci. 2010;35:627–33.
Bao Y, Hata Y, Ikeda M, Withanage K. Mammalian Hippo pathway: from development to cancer and beyond [in process citation]. J Biochem. 2011;149:361–79.
Angus L, Moleirinho S, Herron LR, et al. Willin/FRMD6 expression activates the hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP. Oncogene. 2011. doi:10.1038/onc.2011.224.
Berryman M, Franck Z, Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J Cell Sci. 1993;105:1025–43.
Schwartz-Albiez R, Merling A, Spring H, Moller P, Koretz K. Differential expression of the microspike-associated protein moesin in human tissues. Eur J Cell Biol. 1995;67:189–98.
Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Natl Rev Mol Cell Biol. 2002;3:586–99.
Hunter KW. Ezrin, a key component in tumor metastasis. Trends Mol Med. 2004;10:201–4.
Heiska L, Melikova M, Zhao F, Saotome I, McClatchey AI, Carpen O. Ezrin is key regulator of Src-induced malignant phenotype in three-dimensional environment [epub ahead of print] [record supplied by publisher]. 2011 Oncogene.
Ichikawa T, Masumoto J, Kaneko M, Saida T, Sagara J, Taniguchi S. Expression of moesin and its associated molecule CD44 in epithelial skin tumors. J Cutan Pathol. 1998;25:237–43.
Kobayashi H, Sagara J, Masuumoto J, Kurita H, Kurashina K, Tokunaga J. Shifts in cellular localization of moesin in normal oral epithelium, oral epithelial dysplasia, verrucous carcinoma and oral squamous cell carcinoma. J Oral Pathol Med. 2003;32:344–9.
Kobayashi H, Sagara J, Kurita H, et al. Clinical significance of cellular distribution of moesin in patients with oral squamous cell carcinoma. Clin Cancer Res. 2004;10:572–80.
Madan R, Brandwein-Gensler M, Schlecht NF, et al. Differential tissue and subcellular expression of ERM proteins in normal and malignant tissues: cytoplasmic ezrin expression has prognostic significance for head and neck squamous cell carcinoma. Head Neck. 2006;28:1018–27.
Bruce B, Khanna G, Ren L, et al. Expression of the cytoskeleton linker protein ezrin in human cancers. Clin Exp Metastasis. 2007;24:69–78.
Elzagheid A, Korkeila E, Bendardaf R, et al. Intense cytoplasmic ezrin immunoreactivity predicts poor survival in colorectal cancer. Hum Pathol. 2008;39:1737–43.
Kobel M, Langhammer T, Huttelmaier S, et al. Ezrin expression is related to poor prognosis in FIGO stage I endometrioid carcinomas. Mod Pathol. 2006;19:581–7.
Mhawech-Fauceglia P, Dulguerov P, Beck A, Bonet M, Allal AS. Value of ezrin, maspin and nm 23-H1 protein expressions in predicting outcome of patients with head and neck squamous-cell carcinoma treated with radical radiotherapy. J Clin Pathol. 2007;60:185–9.
Yeh CN, Pang ST, Chen TW, Wu RC, Weng WH, Chen MF. Expression of ezrin is associated with invasion and dedifferentiation of hepatitis B related hepatocellular carcinoma. BMC Cancer. 2009;9:233.
Zhang Y, Hu MY, Wu WZ, et al. The membrane-cytoskeleton organizer ezrin is necessary for hepatocellular carcinoma cell growth and invasiveness. J Cancer Res Clin Oncol. 2006;132:685–97.
Belbin TJ, Singh B, Smith RV, et al. Molecular profiling of tumor progression in head and neck cancer. Arch Otolaryngol Head Neck Surg. 2005;131:10–8.
Schlecht NF, Brandwein-Gensler M, Nuovo GJ, et al. A comparison of clinically utilized human papillomavirus detection methods in head and neck cancer [epub ahead of print] [record supplied by publisher]. Mod Pathol. 2011.
Greenland S, Robins JM. Identifiability, exchangeability, and epidemiological confounding. Int J Epidemiol. 1986;15:413–9.
Lucke CD, Philpott A, Metcalfe JC, et al. Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer. Cancer Res. 2001;61:482–5.
Cullis DN, Philip B, Baleja JD, Feig LA. Rab11-FIP2, an adaptor protein connecting cellular components involved in internalization and recycling of epidermal growth factor receptors. J Biol Chem. 2002;277:49158–66.
Iyer AK, Tran KT, Griffith L, Wells A. Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signaling. J Cell Physiol. 2008;214:504–12.
Haugh JM. Localization of receptor-mediated signal transduction pathways: the inside story. Mol Interv. 2002;2:292–307.
Xu Y, Baker D, Quan T, Baldassare JJ, Voorhees JJ, Fisher GJ. Receptor type protein tyrosine phosphatase-kappa mediates cross-talk between transforming growth factor-beta and epidermal growth factor receptor signaling pathways in human keratinocytes. Mol Biol Cell. 2010;21:29–35.
Chen Y, Knosel T, Ye F, Pacyna-Gengelbach M, Deutschmann N, Petersen I. Decreased PITX1 homeobox gene expression in human lung cancer. Lung Cancer. 2007;55:287–94.
Kolfschoten IG, van Leeuwen B, Berns K, et al. A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell. 2005;121:849–58.
Feng Q, Sekula D, Guo Y, et al. UBE1L causes lung cancer growth suppression by targeting cyclin D1. Mol Cancer Ther. 2008;7:3780–8.
Bennett KL, Romigh T, Arab K, et al. Activator protein 2 alpha (AP2alpha) suppresses 42 kDa C/CAAT enhancer binding protein alpha (p42(C/EBPalpha)) in head and neck squamous cell carcinoma. Int J Cancer. 2009;124:1285–92.
Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol. 2001;21:5500–11.
Toledano-Katchalski H, Kraut J, Sines T, et al. Protein tyrosine phosphatase epsilon inhibits signaling by mitogen-activated protein kinases. Mol Cancer Res. 2003;1:541–50.
Kraut-Cohen J, Muller WJ, Elson A. Protein-tyrosine phosphatase epsilon regulates Shc signaling in a kinase-specific manner: increasing coherence in tyrosine phosphatase signaling. J Biol Chem. 2008;283:4612–21.
Lefort K, Mandinova A, Ostano P, et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev. 2007;21:562–77.
Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333:1154–7.
Wang NJ, Sanborn Z, Arnett KL, et al. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma [in process citation]. Proc Natl Acad Sci USA. 2011;108:17761–6.
Tachibana M, Tonomoto Y, Hyakudomi R, et al. Expression and prognostic significance of EFNB2 and EphB4 genes in patients with oesophageal squamous cell carcinoma. Dig Liver Dis. 2007;39:725–32.
Fujimoto J, Aoki I, Toyoki H, et al. Clinical implications of expression of ETS-1 related to angiogenesis in metastatic lesions of ovarian cancers. Oncology. 2004;66:420–8.
Lee J, Moon HJ, Lee JM, Joo CK. Smad3 regulates Rho signaling via NET1 in the transforming growth factor-beta-induced epithelial-mesenchymal transition of human retinal pigment epithelial cells. J Biol Chem. 2010;285:26618–27.
Lemmers C, Michel D, Lane-Guermonprez L, et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol Biol Cell. 2004;15:1324–33.
Mirza R, Hayasaka S, Takagishi Y, et al. DHCR24 gene knockout mice demonstrate lethal dermopathy with differentiation and maturation defects in the epidermis. J Invest Dermatol. 2006;126:638–47.
Fukui Y, Masuda H, Takagi M, Takahashi K, Kiyokane K. The presence of h2-calponin in human keratinocyte. J Dermatol Sci. 1997;14:29–36.
Kameda H, Watanabe M, Bohgaki M, Tsukiyama T, Hatakeyama S. Inhibition of NF-kappaB signaling via tyrosine phosphorylation of Ymer. Biochem Biophys Res Commun. 2009;378:744–9.
Yamaguchi H, Wang HG. Tissue transglutaminase serves as an inhibitor of apoptosis by cross-linking caspase 3 in thapsigargin-treated cells. Mol Cell Biol. 2006;26:569–79.
Wang Z, Cao N, Nantajit D, Fan M, Liu Y, Li JJ. Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-kappaB regulation. J Biol Chem. 2008;283:21011–23.
Ehsanian R, Brown M, Lu H, et al. YAP dysregulation by phosphorylation or <Np63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets. Oncogene. 2010;29:6160–71.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97:1180–4.
Acknowledgments
Contract grant sponsor: National Institutes of Health; Contract grant numbers: CA103547 (to MBP), CA115243 (to NFS), CA104402 (to TJB); Contract grant sponsor: UK Biotechnology and Biological Sciences Research Council (to FGM). The present study was supported by the Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center. We thank the participants of this study; Catherine Sarta for her time and effort spent enrolling and following participants and with data entry, Gregory Rosenblatt for his assistance with data management and Dr. Joseph Locker for preparation of Fig. 1.
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Schlecht, N.F., Brandwein-Gensler, M., Smith, R.V. et al. Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma. Head and Neck Pathol 6, 232–243 (2012). https://doi.org/10.1007/s12105-011-0328-1
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DOI: https://doi.org/10.1007/s12105-011-0328-1