Top

Published in:

01-02-2014 | Research Article

Functional MUC4 suppress epithelial–mesenchymal transition in lung adenocarcinoma metastasis

Authors: Liuwei Gao, Jun Liu, Bin Zhang, Hua Zhang, Daowei Wang, Tiemei Zhang, Yang Liu, Changli Wang

Published in: Tumor Biology | Issue 2/2014

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.

Available only for authorised users

Nakamura N et al. Identification of tumour markers and differentiation markers for molecular diagnosis of lung adenocarcinoma. Oncogene. 2006;25(30):4245–55.PubMedCrossRef

Feldser DM et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010;468(7323):572–5.PubMedCentralPubMedCrossRef

Chaffer CL, Thompson EW, Williams ED. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs. 2007;185(1–3):7–19.PubMedCrossRef

Kyprianou N. ASK-ing EMT not to spread cancer. Proc Natl Acad Sci U S A. 2010;107(7):2731–2.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

Sato M, Shames DS, Hasegawa Y. Emerging evidence of epithelial-to-mesenchymal transition in lung carcinogenesis. Respirology. 2012;17(7):1048–59.PubMedCrossRef

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.PubMedCrossRef

Puisieux A. Role of epithelial-mesenchymal transition in tumour progression. Bull Acad Natl Med. 2009;193(9):2017–32. discussion 2032–4.PubMed

Lee JM et al. The epithelial–mesenchymal transition: new insights in signalling, development, and disease. J Cell Biol. 2006;172(7):973–81.PubMedCrossRef

10.

Kalluri R, Weinberg RA. The basics of epithelial–mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

14.

Singh AP et al. Inhibition of MUC4 expression suppresses pancreatic tumour cell growth and metastasis. Cancer Res. 2004;64(2):622–30.PubMedCrossRef

15.

Ogata S et al. Mucin gene expression in colonic tissues and cell lines. Cancer Res. 1992;52(21):5971–8.PubMed

16.

Lopez-Ferrer A et al. MUC4 expression is increased in dysplastic cervical disorders. Hum Pathol. 2001;32(11):1197–202.PubMedCrossRef

17.

Shibahara H et al. MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type. Hepatology. 2004;39(1):220–9.PubMedCrossRef

18.

Majhi PD et al. Pathobiological implications of MUC4 in non-small-cell lung cancer. J Thorac Oncol. 2013;8(4):398–407.PubMedCrossRef

19.

Giuntoli RN et al. Mucin gene expression in ovarian cancers. Cancer Res. 1998;58(23):5546–50.PubMed

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.PubMedCrossRef

21.

Weed DT et al. MUC4 and ERBB2 expression in major and minor salivary gland mucoepidermoid carcinoma. Head Neck. 2004;26(4):353–64.PubMedCrossRef

22.

Braun J et al. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene. 2010;29(29):4237–44.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

27.

Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.PubMedCrossRef

28.

Wang C et al. The function of SARI in modulating epithelial–mesenchymal transition and lung adenocarcinoma metastasis. PLoS One. 2012;7(9):e38046.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

33.

Lee W et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature. 2010;465(7297):473–7.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

38.

Tsutsumida H et al. MUC4 expression correlates with poor prognosis in small-sized lung adenocarcinoma. Lung Cancer. 2007;55(2):195–203.PubMedCrossRef

Title: Functional MUC4 suppress epithelial–mesenchymal transition in lung adenocarcinoma metastasis
Authors: Liuwei Gao
Jun Liu
Bin Zhang
Hua Zhang
Daowei Wang
Tiemei Zhang
Yang Liu
Changli Wang
Publication date: 01-02-2014
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 2/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-013-1178-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2014

Serum carbohydrate antigen 19-9 and prognosis of patients with gastric cancer

Combination of E2F-1 promoter-regulated oncolytic adenovirus and cytokine-induced killer cells enhances the antitumor effects in an orthotopic rectal cancer model

Quantitative assessment of the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk

A prospective study of the efficacy of a combination of autologous dendritic cells, cytokine-induced killer cells, and chemotherapy in advanced non-small cell lung cancer patients

Significance and prognostic value of Gli-1 and Snail/E-cadherin expression in progressive gastric cancer

GSTT1 genetic polymorphism and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer