title: Functional MUC4 suppress epithelial-mesenchymal transition in lung adenocarcinoma metastasis.
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.
authors.affiliation: Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China, gaoliuwei198719@sina.com.
authors.forename: Liuwei
authors.initials: L
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Daowei
authors.initials: D
authors.lastname: Wang
authors.forename: Tiemei
authors.initials: T
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Changli
authors.initials: C
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015820:Cadherins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D055264:Mucin-4 / Q000096:biosynthesis / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D015820:Cadherins; C524658:MUC4 protein, human; D055264:Mucin-4; D014746:Vimentin
references.citation: Nature. 2010 Nov 25;468(7323):572-5
references.pmid: 21107428
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2731-2
references.pmid: 20145111
references.citation: Nature. 2010 May 27;465(7297):473-7
references.pmid: 20505728
references.citation: Clin Nucl Med. 2011 Aug;36(8):731-2
references.pmid: 21716036
references.citation: BMC Cancer. 2011 Feb 01;11:49
references.pmid: 21284870
references.citation: J Cell Biol. 2006 Mar 27;172(7):973-81
references.pmid: 16567498
references.citation: J Cell Biol. 2003 Nov 24;163(4):847-57
references.pmid: 14623871
references.citation: Lung Cancer. 2007 Feb;55(2):195-203
references.pmid: 17126950
references.citation: Br J Cancer. 2011 Sep 6;105(6):746-52
references.pmid: 21829191
references.citation: J Mammary Gland Biol Neoplasia. 2001 Jul;6(3):323-37
references.pmid: 11547901
references.citation: Pathol Res Pract. 2006;202(9):639-50
references.pmid: 16843618
references.citation: PLoS One. 2012;7(9):e38046
references.pmid: 23049725
references.citation: Lung Cancer. 2011 Nov;74(2):268-73
references.pmid: 21529987
references.citation: Oncogene. 2010 Jul 22;29(29):4237-44
references.pmid: 20498632
references.citation: Oncogene. 2010 Oct 21;29(42):5741-54
references.pmid: 20697346
references.citation: J Clin Invest. 2009 Jun;119(6):1420-8
references.pmid: 19487818
references.citation: Head Neck. 2004 Apr;26(4):353-64
references.pmid: 15054739
references.citation: Bull Acad Natl Med. 2009 Dec;193(9):2017-32; discussion 2032-4
references.pmid: 20666015
references.citation: Oncogene. 2010 Apr 8;29(14):2047-59
references.pmid: 20101235
references.citation: Cancer Res. 1998 Dec 1;58(23):5546-50
references.pmid: 9850092
references.citation: Laryngoscope. 2004 Aug;114(8 Pt 2 Suppl 101):1-32
references.pmid: 15284539
references.citation: Ann Thorac Surg. 2011 Nov;92(5):1794-804; discussion 1804
references.pmid: 22051275
references.citation: J Thorac Oncol. 2013 Apr;8(4):398-407
references.pmid: 23370366
references.citation: Biochem Biophys Res Commun. 2011 Apr 1;407(1):181-4
references.pmid: 21371426
references.citation: Hepatology. 2004 Jan;39(1):220-9
references.pmid: 14752841
references.citation: Oncogene. 2011 Mar 24;30(12):1436-48
references.pmid: 21057535
references.citation: Respirology. 2012 Oct;17(7):1048-59
references.pmid: 22452538
references.citation: Onkologie. 2011;34(6):326-8
references.pmid: 21625187
references.citation: Nat Rev Cancer. 2002 Jun;2(6):442-54
references.pmid: 12189386
references.citation: Oncogene. 2010 May 13;29(19):2760-71
references.pmid: 20228844
references.citation: Cells Tissues Organs. 2007;185(1-3):7-19
references.pmid: 17587803
references.citation: Oncogene. 2006 Jul 13;25(30):4245-55
references.pmid: 16491115
references.citation: Cancer Res. 1992 Nov 1;52(21):5971-8
references.pmid: 1394223
references.citation: Cancer Res. 2004 Jan 15;64(2):622-30
references.pmid: 14744777
references.citation: Arch Pathol Lab Med. 2007 Apr;131(4):593-8
references.pmid: 17425390
references.citation: Int J Cancer. 2006 Jan 15;118(2):290-301
references.pmid: 16080193
references.citation: Exp Cell Res. 2009 May 1;315(8):1490-504
references.pmid: 19245809
references.citation: Hum Pathol. 2001 Nov;32(11):1197-202
references.pmid: 11727258