Advertisement

Tumor Biology

, Volume 36, Issue 8, pp 6559–6568 | Cite as

Decreased expression of claudin-3 is associated with a poor prognosis and EMT in completely resected squamous cell lung carcinoma

  • Juanjuan Che
  • Yifan Yang
  • Jing Xiao
  • Pengfei Zhao
  • Bo Yan
  • Shuo Dong
  • Bangwei Cao
Research Article

Abstract

The deregulation of claudin-3 has been reported to correlate with the invasion and metastasis of various cancers, but little is known about its expression level and the prognostic value in squamous cell lung carcinoma (SqCC). The purpose of this study is to determine the expression levels and the prognostic value of claudin-3 in completely resected SqCC tissues, and the potential underlying mechanism. The protein expression of claudin-3, E-cadherin, β-catenin, and vimentin in the tumor tissues from 103 patients with surgically resected SqCC was examined using immunohistochemistry, western blots, as well as semi-quantitative estimation. The claudin-3 protein level was significantly associated with E-cadherin, β-catenin, and vimentin protein expression. A decreased claudin-3 protein level was significantly correlated with TNM stage, lymph node metastasis, and disease recurrence. Similarly, downregulation of E-cadherin was significantly correlated with lymph node metastasis and disease recurrence. Decreased β-catenin expression also had a significant correlation with disease recurrence. Univariate analyses indicated that the T stage, lymph node metastasis, the TNM stage, and the expression of claudin-3, β-catenin, and vimentin were significant predictors for overall survival (OS). Moreover, multivariate analyses demonstrated that the TNM stage and protein levels of claudin-3, β-catenin, and vimentin were independent predictors for OS of SqCC patients. Claudin-3 plays an important role in the epithelial–mesenchymal transition of SqCC and might be used as a potential prognostic factor for SqCC.

Keywords

Squamous cell lung carcinoma Claudin-3 Epithelial–mesenchymal transition Prognosis 

Notes

Acknowledgments

This work was supported by Grants No. 81272615 from the Natural Science Foundation of China (to Bangwei Cao), No. 2011-3-007 from the Beijing Municipal Health System High-level Health Person Foundation Project (to Bangwei Cao), and No. yyqdkt2014-11 from the Beijing Friendship Hospital Scientific Research Foundation Project (to Juanjuan Che).

Author contributions

Juanjuan Che performed the experiments and wrote the manuscript. Yifan Yang, Jing Xiao, and Pengfei Zhao designed the experiment and collected the tumor samples. Bo Yan and Shuo Dong analyzed the experimental data. Bangwei Cao directed the work and edited the manuscript.

Conflicts of interest

None

Informed consent

Obtained.

Ethics approval

The study was approved by the Research Ethics Committee of Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Data sharing statement

The authors declare that they have no conflicts of interest. This work is original and not under consideration for publication elsewhere.

References

  1. 1.
    Soini Y. Tight junctions in lung cancer and lung metastasis. A review. Int J Clin Exp Pathol. 2012;5:126–36. PubMed: 22400072.PubMedGoogle Scholar
  2. 2.
    Moore W, Talati R, Bhattacharji P, Bilfinger T. Five-year survival after cryoablation of stage I non-small cell lung cancer in medically inoperable patients. J Vasc Interv Radiol. 2015;26:312–9. PubMed: 25735518.CrossRefPubMedGoogle Scholar
  3. 3.
    Dempke WC, Suto T, Reck M. Targeted therapies for non-small cell lung cancer. Lung Cancer. 2010;67:257–74. PubMed: 19914732.CrossRefPubMedGoogle Scholar
  4. 4.
    Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non–small cell lung cancers. Clin Cancer Res. 2005;11:1167–73. PubMed: 15709185.PubMedGoogle Scholar
  5. 5.
    Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133–44. PubMed: 16014883.CrossRefPubMedGoogle Scholar
  6. 6.
    Nichols LS, Ashfaq R, Iacobuzio-Donahue CA. Claudin 4 protein expression in primary and metastatic pancreatic cancer support for use as a therapeutic target. Am J Clin Pathol. 2004;121:226–30. PubMed: 14983936.CrossRefPubMedGoogle Scholar
  7. 7.
    Resnick MB, Konkin T, Routhier J, Sabo E, Pricolo VE. Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study. Mod Pathol. 2005;18:511–8. PubMed: 15475928.CrossRefPubMedGoogle Scholar
  8. 8.
    Szasz AM, Nemeth Z, Gyorffy B, Micsinai M, Krenacs T, Baranyai Z, et al. Identification of a claudin-4 and E-cadherin score to predict prognosis in breast cancer. Cancer Sci. 2011;102:2248–54. PubMed: 21883696.CrossRefPubMedGoogle Scholar
  9. 9.
    Shang X, Lin X, Alvarez E, Manorek G, Howell SB. Tight junction proteins claudin-3 and claudin-4 control tumor growth and metastases. Neoplasia. 2012;14:974–85. PubMed: 23097631.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chao YC, Pan SH, Yang SC, Yu SL, Che TF, Lin CW, et al. Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med. 2009;179:123–33. PubMed: 18787218.CrossRefPubMedGoogle Scholar
  11. 11.
    Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry J, Scolyer RA, Davies MJ, et al. Overexpression of the cell adhesion molecules DDR1, claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Clin Cancer Res. 2004;10:4427–36. PubMed: 15240533.CrossRefPubMedGoogle Scholar
  12. 12.
    Merikallio H, Kaarteenaho R, Pääkkö P, Lehtonen S, Hirvikoski P, Mäkitaro R, et al. Impact of smoking on the expression of claudins in lung carcinoma. Eur J Cancer. 2011;47:620–30. PubMed: 21106366.CrossRefPubMedGoogle Scholar
  13. 13.
    Moldvay J, Jäckel M, Páska C, Soltész I, Schaff Z, Kiss A. Distinct claudin expression profile in histologic subtypes of lung cancer. Lung Cancer. 2007;57:159–67. PubMed: 17418912.CrossRefPubMedGoogle Scholar
  14. 14.
    Gao F, Duan X, Lu X, Liu Y, Zheng L, Ding Z, et al. Novel binding between pre-membrane protein and claudin-1 is required for efficient dengue virus entry. Biochem Biophys Res Commun. 2010;391:952–7. PubMed: 19962368.CrossRefPubMedGoogle Scholar
  15. 15.
    Van Itallie CM, Betts L, Smedley JG, McClane BA, Anderson JM. Structure of the claudin-binding domain of Clostridium perfringens enterotoxin. J Biol Chem. 2008;283:268–74. PubMed: 17977833.CrossRefPubMedGoogle Scholar
  16. 16.
    Saeki R, Kondoh M, Kakutani H, Matsuhisa K, Takahashi A, Suzuki H, et al. A claudin-targeting molecule as an inhibitor of tumor metastasis. J Pharmacol Exp Ther. 2010;334:576–82. PubMed: 20442222.CrossRefPubMedGoogle Scholar
  17. 17.
    Kupferman ME, Jiffar T, El-Naggar A, Yilmaz T, Zhou G, Xie T, et al. TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma. Oncogene. 2010;29:2047–59. PubMed: 20101235.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, et al. Epithelial–mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2010;101:293–9. PubMed: 19961486.CrossRefPubMedGoogle Scholar
  19. 19.
    Kase S, Sugio K, Yamazaki K, Okamoto T, Yano T, Sugimachi K. Expression of E-cadherin and beta-catenin in human non-small cell lung cancer and the clinical significance. Clin Cancer Res. 2000;6:4789–96. PubMed: 11156236.PubMedGoogle Scholar
  20. 20.
    Choi YS, Shim YM, Kim S-H, Son DS, Lee H-S, Kim GY, et al. Prognostic significance of E-cadherin and beta-catenin in resected stage I non-small cell lung cancer. Eur J Cardiothorac Surg. 2003;24:441–9. PubMed: 12965318.CrossRefPubMedGoogle Scholar
  21. 21.
    Chiu CG, Chan SK, Fang ZA, Masoudi H, Wood-Baker R, Jones SJ, et al. Beta-catenin expression is prognostic of improved non-small cell lung cancer survival. Am J Surg. 2012;203:654–9. PubMed: 22402266.CrossRefPubMedGoogle Scholar
  22. 22.
    Richardson F, Young GD, Sennello R, Wolf J, Argast GM, Mercado P, et al. The evaluation of E-cadherin and vimentin as biomarkers of clinical outcomes among patients with non-small cell lung cancer treated with erlotinib as second- or third-line therapy. Anticancer Res. 2012;32:537–52. PubMed: 22287743.PubMedGoogle Scholar
  23. 23.
    Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 2009;28:151–66. PubMed: 19153669.CrossRefPubMedGoogle Scholar
  24. 24.
    De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh G, et al. Molecular and pathological signatures of epithelial–mesenchymal transitions at the cancer invasion front. Histochem Cell Biol. 2008;130:481–94. PubMed: 18648847.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Merikallio H, Kaarteenaho R, Pääkkö P, Lehtonen S, Hirvikoski P, Mäkitaro R, et al. Zeb1 and twist are more commonly expressed in metastatic than primary lung tumours and show inverse associations with claudins. J Clin Pathol. 2011;64:136–40. PubMed: 21131312.CrossRefPubMedGoogle Scholar
  26. 26.
    Lee KW, Lee NK, Kim JH, Kang MS, Yoo HY, Kim HH, et al. Twist1 causes the transcriptional repression of claudin-4 with prognostic significance in esophageal cancer. Biochem Biophys Res Commun. 2012;423:454–60. PubMed: 22668877.CrossRefPubMedGoogle Scholar
  27. 27.
    Jung JH, Jung CK, Choi HJ. Diagnostic utility of expression of claudins in non-small cell lung cancer: different expression profiles in squamous cell carcinomas and adenocarcinomas. Pathol Res Pract. 2009;205:409–16. PubMed: 19231096.CrossRefPubMedGoogle Scholar
  28. 28.
    Romanov V, Whyard TC, Waltzer WC, Gabig TG. A claudin 3 and claudin 4-targeted Clostridium perfringens protoxin is selectively cytotoxic to PSA-producing prostate cancer cells. Cancer Lett. 2014;351:260–4. PubMed: 24952257.CrossRefPubMedGoogle Scholar
  29. 29.
    Yao Q, Zheng QM, Wen JF, Lü T, Wei MQ, Dai SZ. Target-specific cytotoxic activity of recombinant fusion toxin C-CPE-ETA’ against CLDN-3,4-overexpressing ovarian cancer cells. Zhonghua Zhong Liu Za Zhi. 2010;32:897–902. PubMed: 21223796.PubMedGoogle Scholar
  30. 30.
    Ersoz S, Mungan S, Cobanoglu U, Turgutalp H, Ozoran Y. Prognostic importance of claudin-1 and claudin-4 expression in colon carcinomas. Pathol Res Pract. 2011;207:285–9. PubMed: 21493012.CrossRefPubMedGoogle Scholar
  31. 31.
    Merikallio H, Pääkkö P, Harju T, Soini Y. Claudins 10 and 18 are predominantly expressed in lung adenocarcinomas and in tumors of nonsmokers. Int J Clin Exp Pathol. 2011;4:667–73. PubMed: 22076167.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Prudkin L, Liu DD, Ozburn NC, Sun M, Behrens C, Tang X, et al. Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol. 2009;22:668–78. PubMed: 19270647.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hirata T, Fukuse T, Naiki H, Wada H. Expression of E-cadherin and lymph node metastasis in resected non-small-cell lung cancer. Clin Lung Cancer. 2001;3:134–40. PubMed: 14659029.CrossRefPubMedGoogle Scholar
  34. 34.
    Hommura F, Furuuchi K, Yamazaki K, Ogura S, Kinoshita I, Shimizu M, et al. Increased expression of beta-catenin predicts better prognosis in nonsmall cell lung carcinomas. Cancer. 2002;94:752–8. PubMed: 11857309.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang Y, Han Y, Zheng R, Yu J-H, Miao Y, Wang L, et al. Expression of Frat1 correlates with expression of β-catenin and is associated with a poor clinical outcome in human SCC and AC. Tumour Biol. 2012;33:1437–44. PubMed: 22528942.CrossRefPubMedGoogle Scholar
  36. 36.
    Pirinen RT, Hirvikoski P, Johansson RT, Hollmén S, Kosma VM. Reduced expression of alpha-catenin, beta-catenin, and gamma-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol. 2001;54:391–5. PubMed: 11328840.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhang H, Liu J, Yue D, Gao L, Wang D, Zhang H, et al. Clinical significance of E-cadherin, β-catenin, vimentin and S100A4 expression in completely resected squamous cell lung carcinoma. J Clin Pathol. 2013;66:937–45. PubMed: 23853314.CrossRefPubMedGoogle Scholar
  38. 38.
    Kim SH, Kim JM, Shin M, Kim CW, Huang SM, Kang DW, et al. Correlation of epithelial-mesenchymal transition markers with clinicopathologic parameters in adenocarcinomas and squamous cell carcinoma of the lung. Histol Histopathol. 2012;27:581–91. PubMed: 22419022.PubMedGoogle Scholar
  39. 39.
    Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–28. PubMed: 17508028.CrossRefPubMedGoogle Scholar
  40. 40.
    Angelow S, Ahlstrom R, Yu AS. Biology of claudins. Am J Physiol Renal Physiol. 2008;295:F867–76. PubMed: 18480174.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V, Auvinen P, et al. Transcription factors zeb1, twist and snai1 in breast carcinoma. BMC Cancer. 2011;11:73. PubMed: 21324165.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Juanjuan Che
    • 1
  • Yifan Yang
    • 1
  • Jing Xiao
    • 1
  • Pengfei Zhao
    • 1
  • Bo Yan
    • 2
  • Shuo Dong
    • 3
  • Bangwei Cao
    • 1
  1. 1.Department of Oncology, Beijing Friendship HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Department of Microbiology and ImmunologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  3. 3.Department of MedicineBaylor College of MedicineHoustonUSA

Personalised recommendations