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Tumor Biology

, Volume 35, Issue 2, pp 1335–1341 | Cite as

Functional MUC4 suppress epithelial–mesenchymal transition in lung adenocarcinoma metastasis

  • Liuwei Gao
  • Jun Liu
  • Bin Zhang
  • Hua Zhang
  • Daowei Wang
  • Tiemei Zhang
  • Yang Liu
  • Changli Wang
Research Article

Abstract

The mucin MUC4 is a high molecular weight membrane-bound transmembrane glycoprotein that is frequently detected in invasive and metastatic cancer. The overexpression of MUC4 is associated with increased risks for several types of cancer. However, the functional role of MUC4 is poorly understood in lung adenocarcinoma. Using antisense-MUC4-RNA transfected adenocarcinoma cells, we discovered that the loss of MUC4 expression results in epithelial–mesenchymal transition (EMT). We found morphological alterations and the repression of the epithelial marker E-cadherin in transfected cells. Additionally, the loss of MUC4 caused the upregulation of the mesenchymal marker vimentin compared to control cells. Using a MUC4-knockdown versus control LTEP xenograft mice model (129/sv mice), we also found that EMT happened in lung tissues of MUC4-knockdown-LTEP xenograft mice. Moreover, antisense-MUC4-RNA transfected cells had a significantly increased cellular migration ability in vitro. The loss of MUC4 also occurred in lung adenocarcinoma patients with lymph node metastases. We further investigated MUC4 and found that it plays a critical role in regulating EMT by modulating β-catenin. Taken together, our study reveals a novel role for MUC4 in suppressing EMT and suggests that the assessment of MUC4 may function as a prognostic biomarker and could be a potential therapeutic target for lung adenocarcinoma metastasis.

Keywords

MUC4 Lung adenocarcinoma EMT E-cadherin Vimentin β-catenin 

Notes

Acknowledgments

We thank Yang Wang (Tianjin Medical University of Cancer Institute and Hospital, Tianjin, China) for the assistance on the revision of the manuscript.

Conflicts of interest

None declared.

Supplementary material

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References

  1. 1.
    Nakamura N et al. Identification of tumour markers and differentiation markers for molecular diagnosis of lung adenocarcinoma. Oncogene. 2006;25(30):4245–55.PubMedCrossRefGoogle Scholar
  2. 2.
    Feldser DM et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010;468(7323):572–5.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Chaffer CL, Thompson EW, Williams ED. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs. 2007;185(1–3):7–19.PubMedCrossRefGoogle Scholar
  4. 4.
    Kyprianou N. ASK-ing EMT not to spread cancer. Proc Natl Acad Sci U S A. 2010;107(7):2731–2.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Shintani Y et al. Epithelial to mesenchymal transition is a determinant of sensitivity to chemoradiotherapy in non-small cell lung cancer. Ann Thorac Surg. 2011;92(5):1794–804. discussion 1804.PubMedCrossRefGoogle Scholar
  6. 6.
    Sato M, Shames DS, Hasegawa Y. Emerging evidence of epithelial-to-mesenchymal transition in lung carcinogenesis. Respirology. 2012;17(7):1048–59.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim AN et al. Fyn mediates transforming growth factor-beta1-induced downregulation of E-cadherin in human A549 lung cancer cells. Biochem Biophys Res Commun. 2011;407(1):181–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Puisieux A. Role of epithelial-mesenchymal transition in tumour progression. Bull Acad Natl Med. 2009;193(9):2017–32. discussion 2032–4.PubMedGoogle Scholar
  9. 9.
    Lee JM et al. The epithelial–mesenchymal transition: new insights in signalling, development, and disease. J Cell Biol. 2006;172(7):973–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Kalluri R, Weinberg RA. The basics of epithelial–mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Nozawa N et al. Immunohistochemical alpha- and beta-catenin and E-cadherin expression and their clinicopathological significance in human lung adenocarcinoma. Pathol Res Pract. 2006;202(9):639–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Kwon KY et al. MUC4 expression in non-small cell lung carcinomas: relationship to tumour histology and patient survival. Arch Pathol Lab Med. 2007;131(4):593–8.PubMedGoogle Scholar
  13. 13.
    Carraway KL et al. Muc4/sialomucin complex in the mammary gland and breast cancer. J Mammary Gland Biol Neoplasia. 2001;6(3):323–37.PubMedCrossRefGoogle Scholar
  14. 14.
    Singh AP et al. Inhibition of MUC4 expression suppresses pancreatic tumour cell growth and metastasis. Cancer Res. 2004;64(2):622–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Ogata S et al. Mucin gene expression in colonic tissues and cell lines. Cancer Res. 1992;52(21):5971–8.PubMedGoogle Scholar
  16. 16.
    Lopez-Ferrer A et al. MUC4 expression is increased in dysplastic cervical disorders. Hum Pathol. 2001;32(11):1197–202.PubMedCrossRefGoogle Scholar
  17. 17.
    Shibahara H et al. MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type. Hepatology. 2004;39(1):220–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Majhi PD et al. Pathobiological implications of MUC4 in non-small-cell lung cancer. J Thorac Oncol. 2013;8(4):398–407.PubMedCrossRefGoogle Scholar
  19. 19.
    Giuntoli RN et al. Mucin gene expression in ovarian cancers. Cancer Res. 1998;58(23):5546–50.PubMedGoogle Scholar
  20. 20.
    Weed DT et al. MUC4 and ErbB2 expression in squamous cell carcinoma of the upper aerodigestive tract: correlation with clinical outcomes. Laryngoscope. 2004;114(8 Pt 2 Suppl 101):1–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Weed DT et al. MUC4 and ERBB2 expression in major and minor salivary gland mucoepidermoid carcinoma. Head Neck. 2004;26(4):353–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Braun J et al. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene. 2010;29(29):4237–44.PubMedCrossRefGoogle Scholar
  23. 23.
    Vuoriluoto K et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30(12):1436–48.PubMedCrossRefGoogle Scholar
  24. 24.
    Kupferman ME et al. TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma. Oncogene. 2010;29(14):2047–59.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Hiscox S et al. Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int J Cancer. 2006;118(2):290–301.PubMedCrossRefGoogle Scholar
  26. 26.
    Li J, Zhou BP. Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer. 2011;11:49.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang C et al. The function of SARI in modulating epithelial–mesenchymal transition and lung adenocarcinoma metastasis. PLoS One. 2012;7(9):e38046.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Horn G et al. ERK and PI3K regulate different aspects of the epithelial to mesenchymal transition of mammary tumour cells induced by truncated MUC1. Exp Cell Res. 2009;315(8):1490–504.PubMedCrossRefGoogle Scholar
  30. 30.
    Ponnusamy MP et al. MUC4 mucin-induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells. Oncogene. 2010;29(42):5741–54.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Conacci-Sorrell M et al. Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signalling, Slug, and MAPK. J Cell Biol. 2003;163(4):847–57.PubMedCrossRefGoogle Scholar
  32. 32.
    Asnaghi L et al. E-cadherin negatively regulates neoplastic growth in non-small cell lung cancer: role of Rho GTPases. Oncogene. 2010;29(19):2760–71.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Lee W et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature. 2010;465(7297):473–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Hata A et al. Erlotinib after Gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection. Lung Cancer. 2011;74(2):268–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Longo F et al. Long-term survival in a smoking Caucasian male patient treated with Gefitinib for spinal cord compression secondary to lung cancer. Onkologie. 2011;34(6):326–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Rich AL et al. How do patient and hospital features influence outcomes in small-cell lung cancer in England? Br J Cancer. 2011;105(6):746–52.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Weng JH et al. Pituitary FDG uptake in a patient of lung cancer with bilateral adrenal metastases causing adrenal cortical insufficiency. Clin Nucl Med. 2011;36(8):731–2.PubMedCrossRefGoogle Scholar
  38. 38.
    Tsutsumida H et al. MUC4 expression correlates with poor prognosis in small-sized lung adenocarcinoma. Lung Cancer. 2007;55(2):195–203.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Liuwei Gao
    • 1
    • 2
    • 3
  • Jun Liu
    • 1
    • 2
    • 3
  • Bin Zhang
    • 1
    • 2
    • 3
  • Hua Zhang
    • 1
    • 2
    • 3
  • Daowei Wang
    • 1
    • 2
    • 3
  • Tiemei Zhang
    • 1
    • 2
    • 3
  • Yang Liu
    • 1
    • 2
    • 3
  • Changli Wang
    • 1
    • 2
    • 3
  1. 1.Department of Lung CancerTianjin Medical University Cancer Institute and HospitalTianjinChina
  2. 2.National Clinical Research Centre of CancerTianjinChina
  3. 3.Key Laboratory of Cancer Prevention and TherapyTianjinChina

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