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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

MUC1 in lung adenocarcinoma: cross-sectional genetic and serological study

Authors: Yasushi Horimasu, Nobuhisa Ishikawa, Sonosuke Tanaka, Chihiro Hirano, Hiroshi Iwamoto, Shinichiro Ohshimo, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori, Nobuoki Kohno

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Mucin 1 (MUC1) contributes to the growth and metastasis of various cancers, including lung cancer, and MUC1 gene length polymorphisms are associated with susceptibility to lung cancer and its prognosis. In contrast, the association between rs4072037, a single nucleotide polymorphism in MUC1, and lung cancer has not been well studied.

Methods

In the present study, we determined the rs4072037 genotype and measured serum KL-6 levels to evaluate the association between lung adenocarcinoma (ADC) and rs4072037 or serum KL-6 levels. DNA samples were available for 172 patients and these were included in the genomic analyses. In addition, 304 patients were included in the serum analyses. Furthermore, 276 healthy volunteers were included in both genomic and serum analyses.

Results

The rs4072037 genotype was not associated with susceptibility to lung ADC or its prognosis. Interestingly, serum KL-6 levels significantly differed according to rs4072037 genotype in those with T1 or T2 (P < 0.001), N0 or N1 (P = 0.002) and M0 (P < 0.001), but not in those with T3 or T4 (P = 0.882), N2 or N3 (P = 0.616) and M1a or M1b (P = 0.501). Serum KL-6 levels were significantly associated with the presence of lung ADC, as well as with its progression and prognosis, indicating the crucial involvement of KL-6/MUC1 in the development of lung cancer and its progression.

Conclusion

Based on these findings, we conclude that rs4072037 does not have a significant impact on the pathogenesis or prognosis of lung ADC, whereas serum KL-6 levels, which might reflecting the molecular length of MUC1, are significantly associated with lung ADC.
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Literature
1.
Devesa SS, Bray F, Vizcaino AP, Parkin DM. International lung cancer trends by histologic type: male: female differences diminishing and adenocarcinoma rates rising. Int J Cancer. 2005;117:294–9.CrossRefPubMed
2.
3.
Kohlgraf KG, Gawron AJ, Higashi M, Meza JL, Burdick MD, Kitajima S, et al. Contribution of the MUC1 tandem repeat and cytoplasmic tail to invasive and metastatic properties of a pancreatic cancer cell line. Cancer Res. 2003;63:5011–20.PubMed
4.
Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4:45–60.CrossRefPubMed
5.
Mitsuta K, Yokoyama A, Kondo K, Nakajima M, Arita K, Kohno N. Polymorphism of the MUC1 mucin gene is associated with susceptibility to lung adenocarcinoma and poor prognosis. Oncol Rep. 2005;14:185–9.PubMed
6.
Ligtenberg MJ, Gennissen AM, Vos HL, Hilkens J. A single nucleotide polymorphism in an exon dictates allele dependent differential splicing of episialin mRNA. Nucleic Acids Res. 1991;19:297–301.CrossRefPubMedPubMedCentral
7.
Pratt WS, Islam I, Swallow DM. Two additional polymorphisms within the hypervariable MUC1 gene: association of alleles either side of the VNTR region. Ann Hum Genet. 1996;60:21–8.CrossRefPubMed
8.
Jia Y, Persson C, Hou L, Zheng Z, Yeager M, Lissowska J, et al. A comprehensive analysis of common genetic variation in MUC1, MUC5AC, MUC6 genes and risk of stomach cancer. Cancer Causes Control. 2010;21:313–21.CrossRefPubMedPubMedCentral
9.
Saeki N, Saito A, Choi IJ, Matsuo K, Ohnami S, Totsuka H, et al. A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer. Gastroenterology. 2011;140:892–902.CrossRefPubMed
10.
Hu N, Wang Z, Song X, Wei L, Kim BS, Freedman ND, et al. Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours. Gut 2015:in press
11.
Kohno N, Akiyama M, Kyoizumi S, Hakoda M, Kobuke K, Yamakido M. Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma. Jpn J Clin Oncol. 1988;18:203–16.PubMed
12.
Seko A, Ohkura T, Ideo H, Yamashita K. Novel O-linked glycans containing 6′-sulfo-gal/GalNAc of MUC1 secreted from human breast cancer YMB-S cells: possible carbohydrate epitopes of KL-6(MUC1) monoclonal antibody. Glycobiology. 2012;22:181–95.CrossRefPubMed
13.
Kohno N. Serum marker KL-6/MUC1 for the diagnosis and management of interstitial pneumonitis. J Med Investig. 1999;46:151–8.
14.
Ishikawa N, Hattori N, Yokoyama A, Kohno N. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig. 2012;50:3–13.CrossRefPubMed
15.
Ishikawa N, Hattori N, Yokoyama A, Tanaka S, Nishino R, Yoshioka K, et al. Usefulness of monitoring the circulating Krebs von den Lungen-6 levels to predict the clinical outcome of patients with advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Int J Cancer. 2008;22:2612–20.CrossRef
16.
Tanaka S, Hattori N, Ishikawa N, Shoda H, Takano A, Nishino R, et al. Krebs von den Lungen-6 (KL-6) is a prognostic biomarker in patients with surgically resected nonsmall cell lung cancer. Int J Cancer. 2012;130:377–87.CrossRefPubMed
17.
Suda K, Mitsudomi T. Role of EGFR mutations in lung cancers: prognosis and tumor chemosensitivity. Arch Toxicol. 2015;89:1227–40.CrossRefPubMed
18.
Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, Ito H, et al. Cancer-test Inata J1, Hattori N, Yokoyama A, Ohshimo S, Doi M, Ishikawa N, Hamada H, Kohno Nis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res. 2007;67:1601–11611.CrossRef
19.
Inata J, Hattori N, Yokoyama A, Ohshimo S, Doi M, Ishikawa N, et al. Circulating KL-6/MUC1 mucin carrying sialyl Lewisa oligosaccharide is an independent prognostic factor in patients with lung adenocarcinoma. Int J Cancer. 2007;120:2643–9.CrossRefPubMed
20.
Kawase S, Hattori N, Ishikawa N, Horimasu Y, Fujitaka K, Furonaka O, et al. Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease. Respir Res. 2011;12:97.CrossRefPubMedPubMedCentral
21.
Tanaka S, Hattori N, Ishikawa N, Horimasu Y, Deguchi N, Takano A, et al. Interferon (alpha, beta and omega) receptor 2 is a prognostic biomarker for lung cancer. Pathobiology. 2012;79:24–33.CrossRefPubMed
22.
Sobin LH, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumors. 7th ed. Chichester: Wiley; 2010. 310p.
23.
Nagai Y, Miyazawa H, Huqun, Tanaka T, Udagawa K, Kato M, et al. Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 2005;65:7276–82.CrossRefPubMed
24.
Horimasu Y, Hattori N, Ishikawa N, Kawase S, Tanaka S, Yoshioka K, et al. Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respir Med. 2012;106:1756–64.CrossRefPubMed
25.
Horimasu Y, Hattori N, Ishikawa N, Tanaka S, Bonella F, Ohshimo S, et al. Differences in serum SP-D levels between German and Japanese subjects are associated with SFTPD gene polymorphisms. BMC Med Genet. 2014;15:4.CrossRefPubMedPubMedCentral
26.
Horimasu Y, Ohshimo S, Bonella F, Tanaka S, Ishikawa N, Hattori N, Guzman J, Costabel U, et al. MUC5B promoter polymorphism in Japanese patients with idiopathic pulmonary fibrosis. Respirology. 2015;20:439–44.CrossRefPubMed
27.
Ohshimo S, Yokoyama A, Hattori N, Ishikawa N, Hirasawa Y, Kohno N. KL-6, human MUC1 mucin, promotes proliferation and survival of lung fibroblasts. Biochem Biophys Res Commun. 2005;338:1845–52.CrossRefPubMed
28.
Dunn OJ. Multiple comparisons using rank sums. Technometrics. 1964;6:241–52.CrossRef
29.
Janssen R, Kruit A, Grutters JC, Ruven HJ, Gerritsen WB, van den Bosch JM. The mucin-1 568 adenosine to guanine polymorphism influences serum Krebs von den Lungen-6 levels. Am J Respir Cell Mol Biol. 2006;34:496–9.CrossRefPubMed
30.
Wesseling J, van der Valk SW, Vos HL, Sonnenberg A, Hilkens J. Episialin (MUC1) overexpression inhibits integrin-mediated cell adhesion to extracellular matrix components. J Cell Biol. 1995;29:255–65.CrossRef
31.
Wesseling J, van der Valk SW, Hilkens J. A mechanism for inhibition of E-cadherin-mediated cell-cell adhesion by the membrane-associated mucin episialin/MUC1. Mol Biol Cell. 1996;7:565–77.CrossRefPubMedPubMedCentral
32.
Kohno N, Kyoizumi S, Awaya Y, Fukuhara H, Yamakido M, Akiyama M. New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6. Chest. 1989;96:68–73.CrossRefPubMed
33.
Doi M, Yokoyama A, Kondo K, Ohnishi H, Ishikawa N, Hattori N, et al. Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping. Cancer Sci. 2006;97:420–9.CrossRefPubMed
34.
Imbert Y, Foulks GN, Brennan MD, Jumblatt MM, John G, Shah HA, Newton C, et al. MUC1 and estrogen receptor alpha gene polymorphisms in dry eye patients. Exp Eye Res. 2009;88:334–8.CrossRefPubMed
35.
Shigemura M, Nasuhara Y, Konno S, Shimizu C, Matsuno K, Yamguchi E, et al. Effects of molecular structural variants on serum Krebs von den Lungen-6 levels in sarcoidosis. J Transl Med. 2012;10:111.CrossRefPubMedPubMedCentral
36.
Kim YJ, Varki A. Perspectives on the significance of altered glycosylation of glycoproteins in cancer. Glycoconj J. 1997;14:569–76.CrossRefPubMed
37.
38.
39.
Burchell JM, Mungul A, Taylor-Papadimitriou J. O-linked glycosylation in the mammary gland: changes that occur during malignancy. J Mammary Gland Biol Neoplasia. 2001;6:355–64.CrossRefPubMed
40.
Reticker-Flynn NE, Bhatia S. Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche. Cancer Discov. 2015;5:168–81.CrossRefPubMed
41.
Jonckheere N, Van Seuningen I. The membrane-bound mucins: from cell signalling to transcriptional regulation and expression in epithelial cancers. Biochimie. 2010;92:1–11.CrossRefPubMed
Metadata
Title
MUC1 in lung adenocarcinoma: cross-sectional genetic and serological study
Authors
Yasushi Horimasu
Nobuhisa Ishikawa
Sonosuke Tanaka
Chihiro Hirano
Hiroshi Iwamoto
Shinichiro Ohshimo
Kazunori Fujitaka
Hironobu Hamada
Noboru Hattori
Nobuoki Kohno
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3272-y

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