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Journal of Cancer Research and Clinical Oncology

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01.12.2006 | Original Paper

MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays

verfasst von: Huachuan Zheng, Hiroyuki Takahashi, Takahiko Nakajima, Yoshihiro Murai, Zhengguo Cui, Kazuhiro Nomoto, Koichi Tsuneyama, Yasuo Takano

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 12/2006

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Abstract

Purpose

MUC6 was first discovered by screening a gastric mucosa cDNA library and is expressed in the mucous cells of the neck zone and antral glands of the stomach. The aim of the present study was to clarify whether down-regulation has any clinicopathological or prognostic significance in gastric neoplasia.

Methods

Expression of MUC6, MUC5AC and MUC2 was examined using tissue microarrays for immunohistochemistry in gastric carcinomas (n = 225), adenomas (n = 40), and normal mucosa (n = 89) and compared with clinicopathological parameters and survival data.

Results

MUC6 expression was lower in gastric carcinomas than in adenomas or normal mucosa (P < 0.05) and inversely correlated with tumor size, depth of invasion, lymphatic and venous invasion, lymph node metastasis and UICC staging (P < 0.05). Positive links with expression of MUC2 and MUC5AC were noted (P < 0.05). MUC6 expression was lower in diffuse-type than intestinal-type lesions (P < 0.05). Kaplan–Meier analysis indicated that cumulative survival of patients with no MUC6 expression was significantly lower than with weak, moderate or strong expression in all and even advanced gastric carcinoma (P < 0.05). Multivariate analysis showed three independent prognostic factors, depth of invasion, lymphatic and venous invasion, to concordantly affect the relationship between MUC6 expression and prognosis.

Conclusions

Down-regulation of MUC6 may contribute to malignant transformation of gastric epithelial cells and underlie the molecular bases of growth, invasion, metastasis and differentiation of gastric carcinoma. Altered expression might therefore be employed as an indicator of pathobiological behaviors and prognosis of gastric carcinoma.

Baldus SE, Monig SP, Arkenau V, Hanisch FG, Schneider PM, Thiele J, Holscher AH, Dienes HP (2002) Correlation of MUC5AC immunoreactivity with histopathological subtypes and prognosis of gastric carcinoma. Ann Surg Oncol 9:887–893PubMed

Bartman AE, Buisine MP, Aubert JP, Niehans GA, Toribara NW, Kim YS, Kelly EJ, Crabtree JE, Ho SB (1998) The MUC6 secretory mucin gene is expressed in a wide variety of epithelial tissues. J Pathol 186:398–405PubMedCrossRef

Byrd JC, Bresalier RS (2004) Mucins and mucin binding proteins in colorectal cancer. Cancer Metastasis Rev 23:77–99PubMedCrossRef

Byrd JC, Yunker CK, Xu QS, Sternberg LR, Bresalier RS (2000) Inhibition of gastric mucin synthesis by Helicobacter pylori. Gastroenterology 118:1072–1079PubMedCrossRef

Cozzi PJ, Wang J, Delprado W, Perkins AC, Allen BJ, Russell PJ, Li Y (2005) MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer. Clin Exp Metastasis 22:565–573PubMedCrossRef

Durai Babu S, Jayanthi V, Niranjali D, Reis CA, Devaraj H (2006) Expression profile of mucins (MUC2, MUC5AC and MUC6) in Helicobacter pylori infected pre-neoplastic and neoplastic human gastric epithelium. Mol Cancer 5:10 (in press)

Hamamoto A, Abe Y, Nishi M, Fujimori S, Ohnishi Y, Yamazaki H, Oida Y, Miyazaki N, Inada K, Ueyama Y, Iwasaki M, Inoue H, Nakamura M (2005) Aberrant expression of the gastric mucin MUC6 in human pulmonary adenocarcinoma xenografts. Int J Oncol 26:891–896PubMed

Ho SB, Shekels LL, Toribara NW, Kim YS, Lyftogt C, Cherwitz DL, Niehans GA (1995) Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium. Cancer Res 55:2681–2690PubMed

Ho SB, Takamura K, Anway R, Shekels LL, Toribara NW, Ota H (2004) The adherent gastric mucous layer is composed of alternating layers of MUC5AC and MUC6 mucin proteins. Dig Dis Sci 49:1598–606PubMedCrossRef

zur Hausen A, van Grieken NC, Meijer GA, Hermsen MA, Bloemena E, Meuwissen SG, Baak JP, Meijer CJ, Kuipers EJ, van den Brule AJ (2001) Distinct chromosomal aberrations in Epstein-Barr virus-carrying gastric carcinomas tested by comparative genomic hybridization. Gastroenterology 121:612–618PubMedCrossRef

Kim H, Seo JH, Kim KH (2003) The effect of p38 mitogen-activated protein kinase on mucin gene expression and apoptosis in Helicobacter pylori-infected gastric epithelial cells. Ann N Y Acad Sci 1010:90–94PubMedCrossRef

Kocer B, Soran A, Kiyak G, Erdogan S, Eroglu A, Bozkurt B, Solak C, Cengiz O (2004) Prognostic significance of mucin expression in gastric carcinoma. Dig Dis Sci 49:954–64PubMedCrossRef

Kodama M, Kodama T, Murakami M (2000) Oncogene activation and tumor suppressor gene inactivation find their sites of expression in the changes in time and space of the age-adjusted cancer incidence rate. In Vivo 14:725–734PubMed

Kumada T, Tsuneyama K, Hatta H, Ishizawa S, Takano Y (2004) Improved 1-h rapid immunostaining method using intermittent microwave irradiation: practicability based on 5 years application in Toyama Medical and Pharmaceutical University Hospital. Mod Pathol 17:1141–1149PubMedCrossRef

Lauren P (1965). The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49PubMed

Lee HS, Lee HK, Kim HS, Yang HK, Kim YI, Kim WH (2001) MUC1, MUC2, MUC5AC, and MUC6 expressions in gastric carcinomas: their roles as prognostic indicators. Cancer 92:1427–1434PubMedCrossRef

Mizoshita T, Tsukamoto T, Nakanishi H, Inada K, Ogasawara N, Joh T, Itoh M, Yamamura Y, Tatematsu M (2003) Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol 129:727–734PubMedCrossRef

Pinto-de-Sousa J, David L, Reis CA, Gomes R, Silva L, Pimenta A (2002) Mucins MUC1, MUC2, MUC5AC and MUC6 expression in the evaluation of differentiation and clinico-biological behaviour of gastric carcinoma. Virchows Arch 440:304–310PubMedCrossRef

Pinto-de-Sousa J, Reis CA, David L, Pimenta A, Cardoso-de-Oliveira M (2004) MUC5B expression in gastric carcinoma: relationship with clinico-pathological parameters and with expression of mucins MUC1, MUC2, MUC5AC and MUC6. Virchows Arch 444:224–230PubMedCrossRef

Ranzani GN, Renault B, Pellegata NS, Fattorini P, Magni E, Bacci F, Amadori D (1993) Loss of heterozygosity and K-ras gene mutations in gastric cancer. Hum Genet 92:244–249PubMedCrossRef

Reis CA, David L, Carvalho F, Mandel U, de Bolos C, Mirgorodskaya E, Clausen H, Sobrinho-Simoes M (2000) Immunohistochemical study of the expression of MUC6 mucin and co-expression of other secreted mucins (MUC5AC and MUC2) in human gastric carcinomas. J Histochem Cytochem 48:377–388PubMed

Rousseau K, Byrne C, Kim YS, Gum JR, Swallow DM, Toribara NW (2004) The complete genomic organization of the human MUC6 and MUC2 mucin genes. Genomics 83:936–939PubMedCrossRef

Slomiany BL, Slomiany A (2003) Impedance of Helicobacter pylori lipopolysaccharide interference with gastric mucin synthesis by peroxisome proliferator-activated receptor gamma activation involves phosphatidylinositol 3-kinase/ERK pathway. IUBMB Life 55:97–102PubMed

Slomiany BL, Slomiany A (2005) Up-regulation in endothelin-1 by Helicobacter pylori lipopolysaccharide interferes with gastric mucin synthesis via epidermal growth factor receptor transactivation. Scand J Gastroenterol 40:921–928PubMedCrossRef

Sobin LH, Wittekind CH (2002) TNM classification of malignant tumors, 6th edn. Wiley, Hoboken

Tajima Y, Shimoda T, Nakanishi Y, Yokoyama N, Tanaka T, Shimizu K, Saito T, Kawamura M, Kusano M, Kumagai K (2001) Gastric and intestinal phenotypic marker expression in gastric carcinomas and its prognostic significance: immunohistochemical analysis of 136 lesions. Oncology 61:212–220PubMedCrossRef

Utsunomiya T, Yonezawa S, Sakamoto H, Kitamura H, Hokita S, Aiko T, Tanaka S, Irimura T, Kim YS, Sato E (1998) Expression of MUC1 and MUC2 mucins in gastric carcinomas: its relationship with the prognosis of the patients. Clin Cancer Res 4:2605–2614PubMed

Wang RQ, Fang DC (2006) Effects of Helicobacter pylori infection on mucin expression in gastric carcinoma and pericancerous tissues. J Gastroenterol Hepatol 21:425–431PubMedCrossRef

Titel: MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays
verfasst von: Huachuan Zheng
Hiroyuki Takahashi
Takahiko Nakajima
Yoshihiro Murai
Zhengguo Cui
Kazuhiro Nomoto
Koichi Tsuneyama
Yasuo Takano
Publikationsdatum: 01.12.2006
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 12/2006
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-006-0135-3

Springer Medizin

MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays