Abstract
Purpose
Epithelial–mesenchymal transition (EMT) and p53 play important roles in controlling cancer invasion and metastasis. However, discrepancies still exist in the relationship between the expression of an epithelial marker E-cadherin and predicting short survival of patients in many types of cancer. In this study, we aimed to determine the levels of E-cadherin, Twist, and p53 in tumor tissues from patients with oral squamous cell carcinoma (OSCC) and their clinical significances.
Methods
The protein expression of 112 OSCC tumor and 16 benign tissues was examined by immunohistochemistry staining. Overall survival rates of 112 OSCC patients were measured using Kaplan–Meier estimates and the log-rank tests.
Results
E-cadherin and p53 downregulation were found in 70 of 112 (62.5 %) and 66 of 112 (59.0 %), respectively, and Twist overexpression was found in 72 of 112 (64.3 %) studied cases of OSCC patients. Expression of E-cadherin was significantly associated with tumor location (P = 0.004) and mortality (P = 0.010). Patients with lower E-cadherin expression (P = 0.024), betel quid chewing (P = 0.006), smoking (P = 0.001), tumor size >2 cm (P = 0.001), advanced tumor stage (P = 0.043), and recurrence (P < 0.001) exhibited a poorer outcome. Multivariate analysis showed that E-cadherin is an independent marker for survival prediction. Additionally, low E-cadherin expression is significantly correlated with low p53 expression.
Conclusions
E-cadherin is an independent marker for survival prediction in OSCC. Co-evaluation of E-cadherin and p53 expression might be a valuable tool for predicting OSCC patient outcome.
Similar content being viewed by others
Abbreviations
- EMT:
-
Epithelial–mesenchymal transition
- IHC:
-
Immunohistochemistry
- OSCC:
-
Oral squamous cell carcinoma
References
Aamodt R, Bondi J, Andersen SN, Bakka A, Bukholm G, Bukholm IR (2010) The prognostic impact of protein expression of E-cadherin–catenin complexes differs between rectal and colon carcinoma. Gastroenterol Res Pract. doi:10.1155/2010/616023
Bacic B, Haller H, Mrklic I, Kosta V, Caric A, Tomic S (2013) Prognostic role of E-cadherin in patients with advanced serous ovarian cancer. Arch Gynecol Obstet 287(6):1219–1224. doi:10.1007/s00404-012-2684-9
Bettendorf O, Piffko J, Bankfalvi A (2004) Prognostic and predictive factors in oral squamous cell cancer: important tools for planning individual therapy? Oral Oncol 40(2):110–119
Bondi J, Bukholm G, Nesland JM, Bakka A, Bukholm IR (2006) An increase in the number of adhesion proteins with altered expression is associated with an increased risk of cancer death for colon carcinoma patients. Int J Colorectal Dis 21(3):231–237. doi:10.1007/s00384-005-0762-1
Brinkman BM, Wong DT (2006) Disease mechanism and biomarkers of oral squamous cell carcinoma. Curr Opin Oncol 18(3):228–233. doi:10.1097/01.cco.0000219250.15041.f8
Brooks CL, Gu W (2003) Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 15(2):164–171
Cheng AN, Jiang SS, Fan CC, Lo YK, Kuo CY, Chen CH, Liu YL, Lee CC, Chen WS, Huang TS, Wang TY, Lee AY (2013) Increased Cdc7 expression is a marker of oral squamous cell carcinoma and overexpression of Cdc7 contributes to the resistance to DNA-damaging agents. Cancer Lett 337(2):218–225. doi:10.1016/j.canlet.2013.05.008
Davidson B, Gotlieb WH, Ben-Baruch G, Nesland JM, Bryne M, Goldberg I, Kopolovic J, Berner A (2000) E-cadherin complex protein expression and survival in ovarian carcinoma. Gynecol Oncol 79(3):362–371. doi:10.1006/gyno.2000.5964
Dayan D, Vered M (2013) Is immuno-expression of E-cadherin really a prognostic factor in head and neck cancer? Oral Oncol 49(3):e5. doi:10.1016/j.oraloncology.2012.10.007
Department-of-Health (ed) (2009) Cancer registry annual report in Taiwan. Department of Health, Taipei, Taiwan
Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D, Lopes CS (2004) Prognostic value of E-cadherin immunoexpression in patients with primary ovarian carcinomas. Ann Oncol 15(10):1535–1542. doi:10.1093/annonc/mdh387
Ho CM, Cheng WF, Lin MC, Chen TC, Huang SH, Liu FS, Chien CC, Yu MH, Wang TY, Hsieh CY (2010) Prognostic and predictive values of E-cadherin for patients of ovarian clear cell adenocarcinoma. Int J Gynecol Cancer 20(9):1490–1497. doi:10.1111/IGC.0b013e3181e68a4d
Huber GF, Zullig L, Soltermann A, Roessle M, Graf N, Haerle SK, Studer G, Jochum W, Moch H, Stoeckli SJ (2011) Down regulation of E-cadherin (ECAD)—a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx. BMC Cancer 11(217):211–218. doi:10.1186/1471-2407-11-217
Hung KF, Chang CS, Liu CJ, Lui MT, Cheng CY, Kao SY (2006) Differential expression of E-cadherin in metastatic lesions comparing to primary oral squamous cell carcinoma. J Oral Pathol Med 35(10):589–594. doi:10.1111/j.1600-0714.2006.00474.x
Hung JJ, Yang MH, Hsu HS, Hsu WH, Liu JS, Wu KJ (2009) Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax 64(12):1082–1089. doi:10.1136/thx.2009.115691
Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H, Mori M (2010) Epithelial–mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101(2):293–299. doi:10.1111/j.1349-7006.2009.01419.x
Kim NH, Kim HS, Li XY, Lee I, Choi HS, Kang SE, Cha SY, Ryu JK, Yoon D, Fearon ER, Rowe RG, Lee S, Maher CA, Weiss SJ, Yook JI (2011) A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition. J Cell Biol 195(3):417–433. doi:10.1083/jcb.201103097
Koensgen D, Freitag C, Klaman I, Dahl E, Mustea A, Chekerov R, Braicu I, Lichtenegger W, Sehouli J (2010) Expression and localization of E-cadherin in epithelial ovarian cancer. Anticancer Res 30(7):2525–2530
Kwok WK, Ling MT, Lee TW, Lau TC, Zhou C, Zhang X, Chua CW, Chan KW, Chan FL, Glackin C, Wong YC, Wang X (2005) Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res 65(12):5153–5162. doi:10.1158/0008-5472.can-04-3785
Lim J, Kim JH, Paeng JY, Kim MJ, Hong SD, Lee JI, Hong SP (2005) Prognostic value of activated Akt expression in oral squamous cell carcinoma. J Clin Pathol 58(11):1199–1205. doi:10.1136/jcp.2004.024786
Lim SO, Kim H, Jung G (2010) p53 inhibits tumor cell invasion via the degradation of snail protein in hepatocellular carcinoma. FEBS Lett 584(11):2231–2236. doi:10.1016/j.febslet.2010.04.006
Liu LK, Jiang XY, Zhou XX, Wang DM, Song XL, Jiang HB (2010) Upregulation of vimentin and aberrant expression of E-cadherin/beta-catenin complex in oral squamous cell carcinomas: correlation with the clinicopathological features and patient outcome. Mod Pathol 23(2):213–224. doi:10.1038/modpathol.2009.160
Lydiatt WM, Shah JP, Hoffman HT (2001) AJCC stage groupings for head and neck cancer: should we look at alternatives? A report of the head and neck sites task force. Head Neck 23(8):607–612
Martin TA, Goyal A, Watkins G, Jiang WG (2005) Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 12(6):488–496. doi:10.1245/aso.2005.04.010
Mignogna MD, Fedele S, Lo Russo L (2004) The world cancer report and the burden of oral cancer. Eur J Cancer Prev 13(2):139–142
Moore SR, Johnson NW, Pierce AM, Wilson DF (2000) The epidemiology of mouth cancer: a review of global incidence. Oral Dis 6(2):65–74
Muller PA, Vousden KH, Norman JC (2011) p53 and its mutants in tumor cell migration and invasion. J Cell Biol 192(2):209–218. doi:10.1083/jcb.201009059
Nijkamp MM, Span PN, Hoogsteen IJ, van der Kogel AJ, Kaanders JH, Bussink J (2011) Expression of E-cadherin and vimentin correlates with metastasis formation in head and neck squamous cell carcinoma patients. Radiother Oncol 99(3):344–348. doi:10.1016/j.radonc.2011.05.066
Parkin DM, Pisani P, Ferlay J (1999) Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 80(6):827–841
Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415–428. doi:10.1038/nrc2131
Ren D, Wang M, Guo W, Zhao X, Tu X, Huang S, Zou X, Peng X (2013) Wild-type p53 suppresses the epithelial–mesenchymal transition and stemness in PC-3 prostate cancer cells by modulating miR145. Int J Oncol 42(4):1473–1481. doi:10.3892/ijo.2013.1825
Richmond PJ, Karayiannakis AJ, Nagafuchi A, Kaisary AV, Pignatelli M (1997) Aberrant E-cadherin and alpha-catenin expression in prostate cancer: correlation with patient survival. Cancer Res 57(15):3189–3193
Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Hofler H, Becker KF (2002) Differential expression of the epithelial–mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol 161(5):1881–1891. doi:10.1016/s0002-9440(10)64464-1
Shibata K, Kajiyama H, Ino K, Terauchi M, Yamamoto E, Nawa A, Nomura S, Kikkawa F (2008) Twist expression in patients with cervical cancer is associated with poor disease outcome. Ann Oncol 19(1):81–85. doi:10.1093/annonc/mdm344
Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454. doi:10.1038/nrc822
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial–mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007
Tseng RC, Lee SH, Hsu HS, Chen BH, Tsai WC, Tzao C, Wang YC (2010) SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis. Cancer Res 70(2):543–551. doi:10.1158/0008-5472.can-09-2084
Ueda G, Sunakawa H, Nakamori K, Shinya T, Tsuhako W, Tamura Y, Kosugi T, Sato N, Ogi K, Hiratsuka H (2006) Aberrant expression of beta- and gamma-catenin is an independent prognostic marker in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 35(4):356–361. doi:10.1016/j.ijom.2005.07.023
Umbas R, Isaacs WB, Bringuier PP, Schaafsma HE, Karthaus HF, Oosterhof GO, Debruyne FM, Schalken JA (1994) Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res 54(14):3929–3933
van Oort IM, Tomita K, van Bokhoven A, Bussemakers MJ, Kiemeney LA, Karthaus HF, Witjes JA, Schalken JA (2007) The prognostic value of E-cadherin and the cadherin-associated molecules alpha-, beta-, gamma-catenin and p120ctn in prostate cancer specific survival: a long-term follow-up study. Prostate 67(13):1432–1438. doi:10.1002/pros.20626
Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2(8):594–604. doi:10.1038/nrc864
Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH, Yuan A, Lin CW, Yang SC, Chan WK, Li KC, Hong TM, Yang PC (2009) p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol 11(6):694–704. doi:10.1038/ncb1875
Wu DW, Lee MC, Wang J, Chen CY, Cheng YW, Lee H (2013) DDX3 loss by p53 inactivation promotes tumor malignancy via the MDM2/Slug/E-cadherin pathway and poor patient outcome in non-small-cell lung cancer. Oncogene. doi:10.1038/onc.2013.107
Yang MH, Wu KJ (2008) TWIST activation by hypoxia inducible factor-1 (HIF-1): implications in metastasis and development. Cell cycle (Georgetown, TX) 7(14):2090–2096
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939. doi:10.1016/j.cell.2004.06.006
Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10(3):295–305. doi:10.1038/ncb1691
Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, Peng WL, Wu JC (2009) Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology (Baltimore, MD) 50(5):1464–1474. doi:10.1002/hep.23221
Yu Q, Zhang K, Wang X, Liu X, Zhang Z (2010) Expression of transcription factors snail, slug, and twist in human bladder carcinoma. J Exp Clin Cancer Res 29:119. doi:10.1186/1756-9966-29-119
Yuen HF, Chua CW, Chan YP, Wong YC, Wang X, Chan KW (2007) Significance of TWIST and E-cadherin expression in the metastatic progression of prostatic cancer. Histopathology 50(5):648–658. doi:10.1111/j.1365-2559.2007.02665.x
Zhao Z, Ge J, Sun Y, Tian L, Lu J, Liu M, Zhao Y (2012) Is E-cadherin immunoexpression a prognostic factor for head and neck squamous cell carcinoma (HNSCC)? A systematic review and meta-analysis. Oral Oncol 48(9):761–767. doi:10.1016/j.oraloncology.2012.02.024
Zhou YN, Xu CP, Han B, Li M, Qiao L, Fang DC, Yang JM (2002) Expression of E-cadherin and beta-catenin in gastric carcinoma and its correlation with the clinicopathological features and patient survival. WJG 8(6):987–993
Acknowledgments
The authors thank Dr. S. Nieh from Tri-Service General Hospital for pathological examination assistance. The authors also thank Dr. I-Shou Chang (National Institute of Cancer Research, NHRI, Taiwan) for statistic support and helpful discussion. This study was supported by grant from Mackay Memorial Hospital (MMH9949) and by National Core Facility Program for Biotechnology Grants from National Science Council (NSC 101-2319-B-400-001) in Taiwan. This work was also supported by grants from National Health Research Institutes (102A1-CA-PP-08), National Science Council (NSC 102-2627-M-400-001), and Department of Health (DOH99-TD-C-111-004), Taiwan to A. Y.-L. Lee.
Conflict of interest
None declared.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Fan, CC., Wang, TY., Cheng, YA. et al. Expression of E-cadherin, Twist, and p53 and their prognostic value in patients with oral squamous cell carcinoma. J Cancer Res Clin Oncol 139, 1735–1744 (2013). https://doi.org/10.1007/s00432-013-1499-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-013-1499-9