Tumor Biology

, Volume 36, Issue 8, pp 6139–6148 | Cite as

The clinicopathological significance and potential drug target of E-cadherin in NSCLC

  • Kaize Zhong
  • Weiwen Chen
  • Ning Xiao
  • Jian Zhao
Research Article


Human epithelial cadherin (E-cadherin), a member of transmembrane glycoprotein family, encoded by the E-cadherin gene, plays a key role in cell-cell adhesion, adherent junction in normal epithelial tissues, contributing to tissue differentiation and homeostasis. Although previous studies indicated that inactivation of the E-cadherin is mainly induced by hypermethylation of E-cadherin gene, evidence concerning E-cadherin hypermethylation in the carcinogenesis and development of non-small cell lung carcinoma (NSCLC) remains controversial. In this study, we conducted a meta-analysis to quantitatively evaluate the effects of E-cadherin hypermethylation on the incidence and clinicopathological characteristics of NSCLC. A comprehensive search of PubMed and Embase databases was performed up to October 2014. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized. Our meta-analysis combining 18 published articles demonstrated that the hypermethylation frequencies in NSCLC were significantly higher than those in normal control tissues, OR = 3.55, 95 % confidence interval (CI) = 1.98–6.36, p < 0.0001. Further analysis showed that E-cadherin hypermethylation was not strongly associated with the sex or smoking status in NSCLC patients. In addition, E-cadherin hypermethylation was also not strongly associated with pathological types, differentiated status, clinical stages, or metastatic status in NSCLC patients. The results from the current study indicate that the hypermethylation frequency of E-cadherin in NSCLC is strongly associated with NSCLC incidence and it may be an early event in carcinogenesis of NSCLC. We also discussed the potential value of E-cadherin as a drug target that may bring new direction and hope for cancer treatment through gene-targeted therapy.


NSCLC E-cadherin Tumor suppressor gene Methylation Meta-analysis Odds ratio 


Conflicts of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist. 2008;13 Suppl 1:5–13.CrossRefPubMedGoogle Scholar
  3. 3.
    Ghavifekr Fakhr M, Farshdousti Hagh M, Shanehbandi D, Baradaran B. DNA methylation pattern as important epigenetic criterion in cancer. Genet Res Int. 2013;2013:317569.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Delpu Y, Cordelier P, Cho WC, Torrisani J. DNA methylation and cancer diagnosis. Int J Mol Sci. 2013;14:15029–58.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ma X, Wang YW, Zhang MQ, Gazdar AF. DNA methylation data analysis and its application to cancer research. Epigenomics. 2013;5:301–16.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Walter K, Holcomb T, Januario T, Du P, Evangelista M, et al. DNA methylation profiling defines clinically relevant biological subsets of non-small cell lung cancer. Clin Cancer Res. 2012;18:2360–73.CrossRefPubMedGoogle Scholar
  7. 7.
    Fleischhacker M, Dietrich D, Liebenberg V, Field JK, Schmidt B. The role of DNA methylation as biomarkers in the clinical management of lung cancer. Expert Rev Respir Med. 2013;7:363–83.CrossRefPubMedGoogle Scholar
  8. 8.
    Bussemakers MJ, van Bokhoven A, Mees SG, Kemler R, Schalken JA. Molecular cloning and characterization of the human E-cadherin cDNA. Mol Biol Rep. 1993;17:123–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Rodriguez FJ, Lewis-Tuffin LJ, Anastasiadis PZ. E-cadherin’s dark side: possible role in tumor progression. Biochim Biophys Acta. 2012;1826:23–31.PubMedPubMedCentralGoogle Scholar
  10. 10.
    van RF. Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat Rev Cancer. 2014;14:121–34.CrossRefGoogle Scholar
  11. 11.
    Karayiannakis AJ, Syrigos KN, Chatzigianni E, Papanikolaou S, Alexiou D, et al. Aberrant E-cadherin expression associated with loss of differentiation and advanced stage in human pancreatic cancer. Anticancer Res. 1998;18:4177–80.PubMedGoogle Scholar
  12. 12.
    Zheng Z, Pan J, Chu B, Wong YC, Cheung AL, et al. 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;30:458–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Oka H, Shiozaki H, Kobayashi K, Inoue M, Tahara H, et al. Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res. 1993;53:1696–701.PubMedGoogle Scholar
  14. 14.
    Su CY, Li YS, Han Y, Zhou SJ, Liu ZD. Correlation between expression of cell adhesion molecules CD44 v6 and E-cadherin and lymphatic metastasis in non-small cell lung cancer. Asian Pac J Cancer Prev. 2014;15:2221–4.CrossRefPubMedGoogle Scholar
  15. 15.
    Ponce E, Louie MC, Sevigny MB. Acute and chronic cadmium exposure promotes E-cadherin degradation in MCF7 breast cancer cells. Mol Carcinog. 2014.Google Scholar
  16. 16.
    Schildberg CW, Abba M, Merkel S, Agaimy A, Dimmler A, et al. Gastric cancer patients less than 50 years of age exhibit significant downregulation of E-cadherin and CDX2 compared to older reference populations. Adv Med Sci. 2014;59:142–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. BMC Med. 2012;10:51.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Sculier JP, Ghisdal L, Berghmans T, Branle F, Lafitte JJ, et al. The role of mitomycin in the treatment of non-small cell lung cancer: a systematic review with meta-analysis of the literature. Br J Cancer. 2001;84:1150–5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11:193–206.CrossRefPubMedGoogle Scholar
  20. 20.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    DerSimonian R. Meta-analysis in the design and monitoring of clinical trials. Stat Med. 1996;15:1237–48. discussion 1249–1252.CrossRefPubMedGoogle Scholar
  22. 22.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.CrossRefPubMedGoogle Scholar
  23. 23.
    Zheng SY, Hou JY, Zhao J, Jiang D, Ge JF, et al. Clinical outcomes of downregulation of E-cadherin gene expression in non-small cell lung cancer. Asian Pac J Cancer Prev. 2012;13:1557–61.CrossRefPubMedGoogle Scholar
  24. 24.
    Guzman L, Depix MS, Salinas AM, Roldan R, Aguayo F, et al. Analysis of aberrant methylation on promoter sequences of tumor suppressor genes and total DNA in sputum samples: a promising tool for early detection of COPD and lung cancer in smokers. Diagn Pathol. 2012;7:87.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Begum S, Brait M, Dasgupta S, Ostrow KL, Zahurak M, et al. An epigenetic marker panel for detection of lung cancer using cell-free serum DNA. Clin Cancer Res. 2011;17:4494–503.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sasaki H, Hikosaka Y, Kawano O, Moriyama S, Yano M, et al. Methylation of the DLEC1 gene correlates with poor prognosis in Japanese lung cancer patients. Oncol Lett. 2010;1:283–7.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Vaissiere T, Hung RJ, Zaridze D, Moukeria A, Cuenin C, et al. Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors. Cancer Res. 2009;69:243–52.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Buckingham L, Penfield FL, Kim A, Liptay M, Barger C, et al. PTEN, RASSF1 and DAPK site-specific hypermethylation and outcome in surgically treated stage I and II nonsmall cell lung cancer patients. Int J Cancer. 2010;126:1630–9.PubMedGoogle Scholar
  29. 29.
    Wang G, Hu X, Lu C, Su C, Luo S, et al. Promoter-hypermethylation associated defective expression of E-cadherin in primary non-small cell lung cancer. Lung Cancer. 2008;62:162–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Feng Q, Hawes SE, Stern JE, Wiens L, Lu H, et al. DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2008;17:645–54.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang Y, Zhang D, Zheng W, Luo J, Bai Y, et al. Multiple gene methylation of nonsmall cell lung cancers evaluated with 3-dimensional microarray. Cancer. 2008;112:1325–36.CrossRefPubMedGoogle Scholar
  32. 32.
    Tan SH, Ida H, Lau QC, Goh BC, Chieng WS, et al. Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3. Oncol Rep. 2007;18:1225–30.PubMedGoogle Scholar
  33. 33.
    Kim DS, Kim MJ, Lee JY, Kim YZ, Kim EJ, et al. Aberrant methylation of E-cadherin and H-cadherin genes in nonsmall cell lung cancer and its relation to clinicopathologic features. Cancer. 2007;110:2785–92.CrossRefPubMedGoogle Scholar
  34. 34.
    Gu J, Berman D, Lu C, Wistuba II, Roth JA, et al. Aberrant promoter methylation profile and association with survival in patients with non-small cell lung cancer. Clin Cancer Res. 2006;12:7329–38.CrossRefPubMedGoogle Scholar
  35. 35.
    Nakata S, Sugio K, Uramoto H, Oyama T, Hanagiri T, et al. The methylation status and protein expression of CDH1, p16(INK4A), and fragile histidine triad in nonsmall cell lung carcinoma: epigenetic silencing, clinical features, and prognostic significance. Cancer. 2006;106:2190–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Tsou JA, Shen LY, Siegmund KD, Long TI, Laird PW, et al. Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung. Lung Cancer. 2005;47:193–204.CrossRefPubMedGoogle Scholar
  37. 37.
    Russo AL, Thiagalingam A, Pan H, Califano J, Cheng KH, et al. Differential DNA hypermethylation of critical genes mediates the stage-specific tobacco smoke-induced neoplastic progression of lung cancer. Clin Cancer Res. 2005;11:2466–70.CrossRefPubMedGoogle Scholar
  38. 38.
    Topaloglu O, Hoque MO, Tokumaru Y, Lee J, Ratovitski E, et al. Detection of promoter hypermethylation of multiple genes in the tumor and bronchoalveolar lavage of patients with lung cancer. Clin Cancer Res. 2004;10:2284–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Yanagawa N, Tamura G, Oizumi H, Takahashi N, Shimazaki Y, et al. Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers. Cancer Sci. 2003;94:589–92.CrossRefPubMedGoogle Scholar
  40. 40.
    Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, et al. Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res. 2001;61:249–55.PubMedGoogle Scholar
  41. 41.
    Akhavan-Niaki H, Samadani AA. DNA methylation and cancer development: molecular mechanism. Cell Biochem Biophys. 2013;67:501–13.CrossRefPubMedGoogle Scholar
  42. 42.
    Ponce E, Louie MC, Sevigny MB. Acute and chronic cadmium exposure promotes E-cadherin degradation in MCF7 breast cancer cells. Mol Carcinog. 2014;5:22170.Google Scholar
  43. 43.
    Chang Z, Zhou H, Liu Y. Promoter methylation and polymorphism of E-cadherin gene may confer a risk to prostate cancer: a meta-analysis based on 22 studies. Tumour Biol. 2014;24:24.Google Scholar
  44. 44.
    Wu X, Zhuang YX, Hong CQ, Chen JY, You YJ, et al. Clinical importance and therapeutic implication of E-cadherin gene methylation in human ovarian cancer. Med Oncol. 2014;31:100.CrossRefPubMedGoogle Scholar
  45. 45.
    Ceteci F, Ceteci S, Zanucco E, Thakur C, Becker M, et al. E-cadherin controls bronchiolar progenitor cells and onset of preneoplastic lesions in mice. Neoplasia. 2012;14:1164–77.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Liu Y, Hong Y, Zhao Y, Ismail TM, Wong Y, et al. Histone H3 (lys-9) deacetylation is associated with transcriptional silencing of E-cadherin in colorectal cancer cell lines. Cancer Investig. 2008;26:575–82.CrossRefGoogle Scholar
  47. 47.
    Ling ZQ, Li P, Ge MH, Zhao X, Hu FJ, et al. Hypermethylation-modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer. Int J Mol Med. 2011;27:625–35.CrossRefPubMedGoogle Scholar
  48. 48.
    Patra A, Deb M, Dahiya R, Patra SK. 5-Aza-2'-deoxycytidine stress response and apoptosis in prostate cancer. Clin Epigenetics. 2011;2:339–48.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Liu YY, Han JY, Lin SC, Liu ZY, Jiang WT. Effect of CDH1 gene methylation on transforming growth factor (TGF-beta)-induced epithelial-mesenchymal transition in alveolar epithelial cell line A549. Genet Mol Res. 2014;13.Google Scholar
  50. 50.
    Lopes N, Carvalho J, Duraes C, Sousa B, Gomes M, et al. 1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation. Anticancer Res. 2012;32:249–57.PubMedGoogle Scholar
  51. 51.
    Jiang L, Chan JY, Fung KP. Epigenetic loss of CDH1 correlates with multidrug resistance in human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2012;422:739–44.CrossRefPubMedGoogle Scholar
  52. 52.
    Yi TZ, Li J, Han X, Guo J, Qu Q, et al. DNMT inhibitors and HDAC inhibitors regulate E-cadherin and Bcl-2 expression in endometrial carcinoma in vitro and in vivo. Chemotherapy. 2012;58:19–29.CrossRefPubMedGoogle Scholar
  53. 53.
    Sahai E, Marshall CJ. RHO-GTPases and cancer. Nat Rev Cancer. 2002;2:133–42.CrossRefPubMedGoogle Scholar
  54. 54.
    Vincan E, Barker N. The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clin Exp Metastasis. 2008;25:657–63.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Kaize Zhong
    • 1
  • Weiwen Chen
    • 2
  • Ning Xiao
    • 1
  • Jian Zhao
    • 1
  1. 1.Department of Thoracic SurgeryQilu Hospital of Shandong UniversityJinanChina
  2. 2.Department of Biochemistry and Molecular BiologyMedical School of Shandong UniversityJinanChina

Personalised recommendations