Serum MUC5AC mucin as a potential marker for cholangiocarcinoma
Introduction
Cholangiocarcinoma (CCA), bile duct epithelial cancer, is a relatively rare cancer that almost always presents with an extremely poor prognosis [1]. Whereas CCA is rare in Western countries, it is found frequently in Southeast Asia, especially Northeast Thailand where the liver fluke Opisthorchis viverrini is endemic [2]. The relationship between infection with the liver fluke and CCA is strongly supported by both epidemiological [3], [4] and experimental evidence [5], [6].
Mucins are high molecular weight glycoproteins, which can be divided into secreted and membrane-bound forms. In many human carcinomas, the expression profile of mucins is altered, with certain mucins being up-regulated while others are down-regulated [7], [8]. The majority of CCA in humans are adenocarcinoma and mucin producing [9]. Aberrant and altered mucin expressions in CCA are obvious. Extensively expressed MUC1 apomucin, focally expressed MUC2 apomucin and frequently expressed MUC3 apomucin in the central CCA types have been reported [10]. Also documented are the frequent and aberrant expression of the ‘gastric type’, MUC5/6 apomucin, in biliary epithelial cells with dysplasia [11] and non-invasive CCA [9], [10], [12], [13]. Immunohistochemical studies have revealed that MUC5AC mucins are associated with the type and histological grading of the cancer [11] and the cirrhotic condition of the patient [9].
Our study provides the first evidence that MUC5AC apomucin, frequently and aberrantly expressed in CCA, can be detected with high sensitivity and specificity in the serum of CCA patients as compared to those with benign hepatobiliary diseases and hepato-gastrointestinal cancers. Moreover, the apomucin was not detected in the serum of healthy persons. The presence of serum MUC5AC corresponded well with the immunohistochemistry of individual CCA subjects.
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Subjects
Patients undergoing surgical resection of hepato-gastrointestinal cancer at the Department of Surgery, Faculty of Medicine, Khon Kaen University, between 1998 and 1999, were asked to volunteer in the study. Informed consent was obtained from each subject. The Ethics of Human Research Committee, Khon Kaen University, approved details of the study. Preoperative serum was obtained from 179 patients with CCA, 60 with hepato-pancreato-gastrointestinal cancer, and 62 with benign hepatobiliary
Results
Gel-forming mucins are responsible for the viscoelastic properties of the mucus gels found on the epithelial surfaces of the body. These macromolecules have an oligomeric structure stabilized by disulphide bonds and can be depolymerized by treatment with a reducing agent [17]. Agarose gel electrophoresis of unreduced MUC5AC mucins exhibited a major band just entering the gel with evidence of a ‘ladder’ of faster-migrating minor bands (Fig. 1, lane 2). Reduction of MUC5AC mucin with DTT yielded
Discussion
Biliary epithelial cells in the intrahepatic large bile ducts constantly expressed MUC3, MUC6 and MUC5B apomucin, whereas MUC5AC, a secretory mucin found in abundance in gastric mucosa, is rarely expressed [11], [18], [19]. In CCA, extensively expressed MUC1 apomucin and focally expressed MUC2 apomucin were documented [11]. MUC5/6 apomucin and MUC5AC apomucin were more frequently expressed in 70.9% [10] and 57.1% [20] of CCA tumor tissues, respectively. Our MUC5AC immunohistochemistry data
Acknowledgements
This project was supported by The Thailand Research Fund (BRG/06/2544) and Khon Kaen University (44-03-01-04). C. Boonla expresses his gratitude to The Royal Jubilee-PhD Program. We thank Mr. Bryan Roderick Hamman for assistance with the English language presentation.
References (31)
- et al.
Abnormal expression of MUC1 apomucin and mature MUC1 mucin in biliary epithelial cells in various cystic liver diseases
Hepatology
(1996) - et al.
Characterization of apomucin expression in intrahepatic cholangiocarcinomas and their precursor lesions: an immunohistochemical study
Hepatology
(1996) - et al.
Diversity of mucin genes, structure, function, and expression
Gastroenterology
(1995) - et al.
Mucin gene expression in biliary epithelial cells
J. Hepatol.
(1997) - et al.
Liver, gallbladder, extrahepatic bile ducts, and pancreas
Cancer
(1995) - et al.
A high incidence of liver cancer in Khon Kaen Province, Thailand
Southeast Asian J. Trop. Med. Public Health
(1990) - et al.
Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention
Cancer Epidemiol. Biomarkers Prev.
(1993) - et al.
Cross-sectional study of Opisthorchis viverrini infection and cholangiocarcinoma in communities within a high-risk area in northeast Thailand
Int. J. Cancer
(1994) - et al.
Association of liver fluke (Opisthorchis viverrini) infestation with increased expression of cytochrome P450 and carcinogen metabolism in male hamster liver
Mol. Carcinog.
(1994) - et al.
Increased nitrosamine and nitrate biosynthesis mediated by nitric oxide synthase induced in hamsters infected with liver fluke (Opisthorchis viverrini)
Carcinogenesis
(1994)