Molecular Diagnosis & Therapy

, Volume 22, Issue 5, pp 523–535 | Cite as

The Role of E-Cadherin as a Prognostic Biomarker in Head and Neck Squamous Carcinoma: A Systematic Review and Meta-Analysis

  • Javad Yazdani
  • Mohhamad Ali Ghavimi
  • Elahe Jabbari Hagh
  • Farzin AhmadpourEmail author
Systematic Review



In this study, we systematically investigated and analyzed articles focusing on the prognostic value of E-cadherin (E-cad) in human head and neck squamous cell carcinoma (HNSCC).


Searching through the different databases, the studies examining the associations between E-cad and HNSCC prognosis were identified. Outcomes such as disease-specific survival and overall survival were considered acceptable. Hazard ratio (HR) with 95% confidence interval (CI) was used to demonstrate prognostic value.


A total of 40 studies were systematically analyzed, and finally, 1939 subjects were included in our meta-analysis. Our findings showed that significant aberrant expression of E-cad was associated with poor survival. However, some studies showed increased expression of E-cad in metastatic lesions was associated with poor prognosis. Alteration in location of E-cad expression also showed significant association with cancer survival, i.e., increased cytoplasmic E-cad. We conducted a meta-analysis on the eligible articles using a random effect model because of moderate heterogeneity. Strong association between aberrant expression of E-cad and poor survival was demonstrated (pooled HR = 2.28; 95% CI 1.78–2.91).


Aberrant expression of E-cad may be a promising prognostic signature for HNSCC, especially when it is used with other prognostic markers.


Compliance with Ethical Standards


Non funding to declare.

Conflict of interest

None declared by all authors: Javad Yazdani, Mohhamad Ali Ghavimi, Elahe Jabbari Hagh and Farzin Ahmadpour.

Supplementary material

40291_2018_351_MOESM1_ESM.pdf (83 kb)
Supplementary material 1 (PDF 83 kb)
40291_2018_351_MOESM2_ESM.pdf (96 kb)
Supplementary material 2 (PDF 96 kb)


  1. 1.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300. Scholar
  2. 2.
    Hardisson D. Molecular pathogenesis of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2003;260(9):502–8. Scholar
  3. 3.
    Chin D, Boyle GM, Porceddu S, Theile DR, Parsons PG, Coman WB. Head and neck cancer: past, present and future. Expert Rev Anticancer Ther. 2006;6(7):1111–8. Scholar
  4. 4.
    Zhao Z, Ge J, Sun Y, Tian L, Lu J, Liu M, et al. Is E-cadherin immunoexpression a prognostic factor for head and neck squamous cell carcinoma (HNSCC)? A systematic review and meta-analysis. Oral Oncol. 2012;48(9):761–7. Scholar
  5. 5.
    Luo SL, Xie YG, Li Z, Ma JH, Xu X. E-cadherin expression and prognosis of oral cancer: a meta-analysis. Tumour Biol. 2014;35(6):5533–7. Scholar
  6. 6.
    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. Scholar
  7. 7.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.CrossRefPubMedGoogle Scholar
  8. 8.
    (US), N. C. f. B. I. (2005). PubMed Help [Internet].
  9. 9.
    Bosch FX, Andl C, Abel U, Kartenbeck J. E-cadherin is a selective and strongly dominant prognostic factor in squamous cell carcinoma: a comparison of E-cadherin with desmosomal components. Int J Cancer. 2005;114(5):779–90. Scholar
  10. 10.
    Bowie GL, Caslin AW, Roland NJ, Field JK, Jones AS, Kinsella AR. Expression of the cell-cell adhesion molecule E-cadherin in squamous cell carcinoma of the head and neck. Clin Otolaryngol Allied Sci. 1993;18(3):196–201.CrossRefPubMedGoogle Scholar
  11. 11.
    Greco A, De Virgilio A, Rizzo MI, Pandolfi F, Rosati D, de Vincentiis M. The prognostic role of E-cadherin and beta-catenin overexpression in laryngeal squamous cell carcinoma. Laryngoscope. 2016;126(4):E148–55. Scholar
  12. 12.
    Muller S, Su L, Tighiouart M, Saba N, Zhang H, Shin DM, et al. Distinctive E-cadherin and epidermal growth factor receptor expression in metastatic and nonmetastatic head and neck squamous cell carcinoma: predictive and prognostic correlation. Cancer. 2008;113(1):97–107. Scholar
  13. 13.
    Kim CH, Kim J, Kahng H, Choi EC. Change of E-cadherin by hepatocyte growth factor and effects on the prognosis of hypopharyngeal carcinoma. Ann Surg Oncol. 2007;14(5):1565–74. Scholar
  14. 14.
    Zou J, Yang H, Chen F, Zhao H, Lin P, Zhang J, et al. Prognostic significance of fascin-1 and E-cadherin expression in laryngeal squamous cell carcinoma. Eur J Cancer Prev. 2010;19(1):11–7. Scholar
  15. 15.
    Pyo SW, Hashimoto M, Kim YS, Kim CH, Lee SH, Johnson KR, et al. Expression of E-cadherin, P-cadherin and N-cadherin in oral squamous cell carcinoma: correlation with the clinicopathologic features and patient outcome. J Craniomaxillofac Surg. 2007;35(1):1–9. Scholar
  16. 16.
    Muramatsu H, Akimoto T, Maebayashi K, Kita M, Mitsuhashi N. Prognostic significance of dysadherin and E-cadherin expression in patients with head and neck cancer treated by radiation therapy. Anticancer Res. 2008;28(6B):3859–64.PubMedGoogle Scholar
  17. 17.
    Diniz-Freitas M, Garcia-Caballero T, Antunez-Lopez J, Gandara-Rey JM, Garcia-Garcia A. Reduced E-cadherin expression is an indicator of unfavourable prognosis in oral squamous cell carcinoma. Oral Oncol. 2006;42(2):190–200. Scholar
  18. 18.
    Pannone G, Santoro A, Feola A, Bufo P, Papagerakis P, Lo Muzio L, et al. The role of E-cadherin down-regulation in oral cancer: CDH1 gene expression and epigenetic blockage. Curr Cancer Drug Targets. 2014;14(2):115–27.CrossRefPubMedGoogle Scholar
  19. 19.
    Ukpo OC, Thorstad WL, Zhang Q, Lewis JS Jr. Lack of association of cadherin expression and histopathologic type, metastasis, or patient outcome in oropharyngeal squamous cell carcinoma: a tissue microarray study. Head Neck Pathol. 2012;6(1):38–47. Scholar
  20. 20.
    Zheng Z, Pan J, Chu B, Wong YC, Cheung AL, Tsao SW. Downregulation and abnormal expression of E-cadherin and beta-catenin in nasopharyngeal carcinoma: close association with advanced disease stage and lymph node metastasis. Hum Pathol. 1999;30(4):458–66.CrossRefPubMedGoogle Scholar
  21. 21.
    Liu LK, Jiang XY, Zhou XX, Wang DM, Song XL, Jiang HB. 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. 2010;23(2):213–24. Scholar
  22. 22.
    Xie LQ, Bian LJ, Li Z, Li Y, Li ZX, Li B. Altered expression of E-cadherin by hepatocyte growth factor and effect on the prognosis of nasopharyngeal carcinoma. Ann Surg Oncol. 2010;17(7):1927–36. Scholar
  23. 23.
    Fan HX, Wang S, Zhao H, Liu N, Chen D, Sun M, et al. Sonic hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression. Med Oncol. 2014;31(7):41. Scholar
  24. 24.
    Xu XL, Ling ZQ, Chen SZ, Li B, Ji WH, Mao WM. The impact of E-cadherin expression on the prognosis of esophageal cancer: a meta-analysis. Dis Esophagus. 2014;27(1):79–86. Scholar
  25. 25.
    Hung KF, Chang CS, Liu CJ, Lui MT, Cheng CY, Kao SY. Differential expression of E-cadherin in metastatic lesions comparing to primary oral squamous cell carcinoma. J Oral Pathol Med. 2006;35(10):589–94. Scholar
  26. 26.
    Zhong LP, Li J, Zhang CP, Zhu HG, Sun J, Zhang ZY. Expression of E-cadherin in cervical lymph nodes from primary oral squamous cell carcinoma patients. Arch Oral Biol. 2007;52(8):740–7. Scholar
  27. 27.
    Munoz-Guerra MF, Marazuela EG, Fernandez-Contreras ME, Gamallo C. P-cadherin expression reduced in squamous cell carcinoma of the oral cavity: an indicatior of poor prognosis. Cancer. 2005;103(5):960–9. Scholar
  28. 28.
    Ueda G, Sunakawa H, Nakamori K, Shinya T, Tsuhako W, Tamura Y, et al. Aberrant expression of beta- and gamma-catenin is an independent prognostic marker in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2006;35(4):356–61. Scholar
  29. 29.
    Rodrigo JP, Dominguez F, Alvarez C, Manrique C, Herrero A, Suarez C. Expression of E-cadherin in squamous cell carcinomas of the supraglottic larynx with correlations to clinicopathological features. Eur J Cancer. 2002;38(8):1059–64.CrossRefPubMedGoogle Scholar
  30. 30.
    Ahmed RA, Shawky Ael A, Hamed RH. Prognostic significance of cyclin D1 and E-cadherin expression in laryngeal squamous cell carcinoma. Pathol Oncol Res. 2014;20(3):625–33. Scholar
  31. 31.
    Massarelli E, Brown E, Tran NK, Liu DD, Izzo JG, Lee JJ, et al. Loss of E-cadherin and p27 expression is associated with head and neck squamous tumorigenesis. Cancer. 2005;103(5):952–9. Scholar
  32. 32.
    Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, et al. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res. 2004;10(1 Pt 1):166–72.CrossRefPubMedGoogle Scholar
  33. 33.
    da Silva SD, Morand GB, Alobaid FA, Hier MP, Mlynarek AM, Alaoui-Jamali MA, et al. Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma. Clin Exp Metastasis. 2015;32(1):55–63. Scholar
  34. 34.
    Huber GF, Zullig L, Soltermann A, Roessle M, Graf N, Haerle SK, et al. 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. 2011;11(217):211–8. Scholar
  35. 35.
    Chang HW, Chow V, Lam KY, Wei WI, Yuen A. Loss of E-cadherin expression resulting from promoter hypermethylation in oral tongue carcinoma and its prognostic significance. Cancer. 2002;94(2):386–92. Scholar
  36. 36.
    Kurtz KA, Hoffman HT, Zimmerman MB, Robinson RA. Decreased E-cadherin but not beta-catenin expression is associated with vascular invasion and decreased survival in head and neck squamous carcinomas. Otolaryngol Head Neck Surg. 2006;134(1):142–6. Scholar
  37. 37.
    Wang X, Zhang J, Fan M, Zhou Q, Deng H, Aisharif MJ, et al. The expression of E-cadherin at the invasive tumor front of oral squamous cell carcinoma: immunohistochemical and RT-PCR analysis with clinicopathological correlation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107(4):547–54. Scholar
  38. 38.
    Wang C, Liu X, Chen Z, Huang H, Jin Y, Kolokythas A, et al. Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma. Mol Carcinog. 2013;52(3):229–36. Scholar
  39. 39.
    Fan CC, Wang TY, Cheng YA, Jiang SS, Cheng CW, Lee AY, 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. 2013;139(10):1735–44. Scholar
  40. 40.
    Zuo J, Wen J, Lei M, Wen M, Li S, Lv X, et al. Hypoxia promotes the invasion and metastasis of laryngeal cancer cells via EMT. Med Oncol. 2016;33(2):15. Scholar
  41. 41.
    Zhao D, Tang XF, Yang K, Liu JY, Ma XR. Over-expression of integrin-linked kinase correlates with aberrant expression of Snail, E-cadherin and N-cadherin in oral squamous cell carcinoma: implications in tumor progression and metastasis. Clin Exp Metastasis. 2012;29(8):957–69. Scholar
  42. 42.
    Wang C, Liu X, Huang H, Ma H, Cai W, Hou J, et al. Deregulation of Snai2 is associated with metastasis and poor prognosis in tongue squamous cell carcinoma. Int J Cancer. 2012;130(10):2249–58. Scholar
  43. 43.
    Foschini MP, Cocchi R, Morandi L, Marucci G, Pennesi MG, Righi A, et al. E-cadherin loss and Delta Np73L expression in oral squamous cell carcinomas showing aggressive behavior. Head Neck. 2008;30(11):1475–82. Scholar
  44. 44.
    Rodrigo JP, Dominguez F, Suarez V, Canel M, Secades P, Chiara MD. Focal adhesion kinase and E-cadherin as markers for nodal metastasis in laryngeal cancer. Arch Otolaryngol Head Neck Surg. 2007;133(2):145–50. Scholar
  45. 45.
    Liu S, Ye D, Guo W, Yu W, He Y, Hu J, et al. G9a is essential for EMT-mediated metastasis and maintenance of cancer stem cell-like characters in head and neck squamous cell carcinoma. Oncotarget. 2015;6(9):6887–901. Scholar
  46. 46.
    Wang C, Huang H, Huang Z, Wang A, Chen X, Huang L, et al. Tumor budding correlates with poor prognosis and epithelial-mesenchymal transition in tongue squamous cell carcinoma. J Oral Pathol Med. 2011;40(7):545–51. Scholar
  47. 47.
    Rosado P, Lequerica-Fernandez P, Fernandez S, Allonca E, Villallain L, de Vicente JC. E-cadherin and beta-catenin expression in well-differentiated and moderately-differentiated oral squamous cell carcinoma: relations with clinical variables. Br J Oral Maxillofac Surg. 2013;51(2):149–56. Scholar
  48. 48.
    Nakanishi Y, Akimoto S, Sato Y, Kanai Y, Sakamoto M, Hirohashi S. Prognostic significance of dysadherin expression in tongue cancer: immunohistochemical analysis of 91 cases. Appl Immunohistochem Mol Morphol. 2004;12(4):323–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Oral and Maxillofacial Surgery, Faculty of DentistryTabriz University of Medical SciencesTabrizIran
  2. 2.Department of Internal MedicineTabriz University of Medical SciencesTabrizIran

Personalised recommendations