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At least 19 recordsLinked to original sources
PubMed1997

Localization and up-regulation of mucin (MUC2) gene expression in human nasal biopsies of patients with cystic fibrosis.

Using digoxigenin-UTP-labelled human HAM-1 (92 bp) or SMUC41 (850 bp) cRNA probes, the expression and localization of MUC2 gene transcripts were determined by in situ hybridization in human nasal tissues obtained as biopsies from 12 patients with cystic fibrosis (CF): all had been part of a gene therapy trial in which CFTR cDNA-liposome complexes had been delivered by topical application to eight and liposome alone to four as a placebo control. For comparison, there were nasal tissues taken at surgical resection from four non-CF subjects and a further four biopsies taken from normal healthy volunteer controls. Both SMUC41 and HAM-1 probes provided a strong signal. MUC2 mRNA transcripts were present in serous and mucous acini of submucosal glands, ciliated and basal cells of the surface epithelium, and occasional mononuclear inflammatory cells. The percentages (mean +/- SEM) of serous and mucous acini showing positivity for MUC2 gene expression in the four samples surgically resected from non-CF subjects were 25.4 +/- 5.6 and 26.7 +/- 3.3 per cent, respectively. Compared with the non-CF subjects, the mean percentage of acini showing MUC2 gene expression in the four placebo-treated CF subjects was significantly higher for serous (80.5 +/- 12.7 per cent; P < 0.05, t-test), but not for mucous acini (53.1 +/- 16.8 per cent; P = 0.38). In CF and non-CF groups, where present, MUC2 positivity was strongly expressed and constituted approximately 84 per cent of the cell area in serous acini, whereas it was less obvious and was confined to the perinuclear area of cells in mucous acini. A significantly greater proportion of the surface epithelium was positive for MUC2 mRNA transcripts in the CF subjects (89.0, +/- 1.4 per cent) than in the surgically resected tissues of the four non-CF subjects (19.4, +/- 4.0 per cent) (P = 0.02). In the eight CFTR-cDNA-treated subjects, there was an overall trend to reduction, but no statistically significant alteration of MUC2 gene expression. It is concluded that the MUC2 gene is expressed at three- to four-fold higher levels in CF nasal mucosa than in non-CF nasal tissue and that it is expressed in a variety of cells additional to submucosal mucus-secreting glands.

Adult↗
PubMed1997

Overexpression or ectopic expression of MUC2 is the common property of mucinous carcinomas of the colon, pancreas, breast, and ovary.

Mucinous carcinomas of the colorectum have been reported to overexpress the intestinal mucin MUC2. The purpose of this study was to determine whether this alteration is shared by mucinous tumours of the ovary, breast, and pancreas. A total of 40 breast carcinomas (22 of mucinous and 18 of ductal invasive type), 39 ovarian adenocarcinomas (16 mucinous, 23 serous), 47 colorectal carcinomas (25 mucinous and 22 non-mucinous), and 41 pancreatic adenocarcinomas (14 mucinous, 27 non-mucinous) were investigated by immunohistochemistry with the anti-MUC2 monoclonal antibody 4F1 and the expression pattern was ranked. MUC2 mucin is expressed in the normal colonic epithelium; in the normal epithelium of the breast, ovary, and pancreas, it was not detectable by immunohistochemistry or by reverse transcriptase-polymerase chain reaction (RT-PCR). In agreement with previous reports, the colonic mucinous carcinomas differed significantly from the non-mucinous carcinomas by strong MUC2 expression. In all mucinous carcinomas of the ovary, breast, and pancreas, de novo expression of the MUC2 gene was observed, which differentiated mucinous and non-mucinous carcinomas of these tissues (P < 0.001). The overexpression or ectopic expression of the MUC2 gene exhibited by mucinous carcinomas of four organs indicates a common genetic lesion associated with the mucinous tumour phenotype.

Adenocarcinoma, Mucinous↗
PubMed1997

Low O-acetylation of sialyl-Le(x) contributes to its overexpression in colon carcinoma metastases.

Two factors potentially determining the consistent overexpression of sialyl-Le(x) antigen in colon carcinoma and metastases were investigated: (i) the expression of the mucins MUC1 and MUC2, known to carry sialyl-Le(x), by Northern blotting; (ii) the extent of sialic acid O-acetylation, by Western blotting and HPLC. RNA and sialyl-Le(x)-positive mucins were purified from normal colonic mucosa (N), primary carcinomas (T) and their liver metastases (M). Northern blots showed that mRNA expression both of MUC1 and of MUC2 decreases during the progression of the disease, and is lowest in metastatic tissue. The expression of mucin-bound sialyl-Le(x) increased strongly from N to T and, to a lesser extent, to M. After alkali treatment of the mucins these differences disappeared, indicating that the total amount of mucin-bound sialyl-Le(x) is the same in the 3 types of tissues. The O-acetylation of mucin-bound sialyl-Le(x) gradually decreased from N to M. HPLC analysis showed that in N about 70%, in T 45% and in M only 20% of mucin-bound sialic acids are O-acetylated. Thus, the increase of sialyl-Le(x) detectable during colon-carcinoma progression is due to diminished O-acetylation and not to increased expression of mucin protein cores. The decrease of O-acetylation is therefore the primary chemical alteration contributing to colon carcinoma-associated overexpression of sialyl-Le(x).

Acetylation↗
PubMed1993

Immunohistochemical study of mucin carbohydrates and core proteins in human pancreatic tumors.

BACKGROUND: Pancreatic cancer has a poor prognosis, and early diagnosis of carcinoma and discrimination between malignant and benign conditions are difficult. Many pancreatic cancer-associated antigens, such as CA 19-9, DU-PAN-2, YPan-1, and SPan-1, have been studied. However, expression of Tn, sialosyl-Tn, and T antigens in tissues of different types of pancreatic neoplasms has not been investigated systematically. Moreover, little is known about the distribution of different types of apomucins in the pancreas. METHODS: The expression of Tn, sialosyl-Tn, and T antigens and DF3 (mammary type apomucin) and intestinal MRP (intestinal type apomucin) was examined immunohistochemically in 47 pancreatic tumors: 36 invasive ductal carcinomas, 5 intraductal papillary tumors, and 6 adenomas. RESULTS: In normal pancreatic tissues, neither Tn nor sialosyl-Tn antigen was expressed. In contrast, expression of both Tn and sialosyl-Tn antigens was observed in all the invasive ductal carcinomas and intraductal papillary tumors. None of the adenomas expressed both Tn and sialosyl-Tn. DF3 antigen was expressed in all invasive ductal carcinomas but not in intraductal papillary tumors, whereas intestinal MRP was expressed in all the intraductal papillary tumors but not in the invasive ductal carcinomas. CONCLUSIONS: The results from this study suggest that the expression of the mucin core protein and mucin carbohydrate antigens is correlated with the biologic behavior of pancreatic tumors. In particular, the expression of mammary type mucin core protein and intestinal type mucin core protein showed a striking contrast between invasive ductal carcinomas with a poor prognosis and intraductal papillary tumors with a favorable prognosis.

Adenoma↗
PubMed1993

Immunohistochemical study of mucin carbohydrates and core proteins in hepatolithiasis and cholangiocarcinoma.

The expression of mucin carbohydrates [Tn, sialosyl-Tn(STn), and T antigens] and core proteins [MUCI-apomucin-related antigen (ARA) and MUC2-ARA] was examined immunohistochemically in tissues from 40 patients with hepatolithiasis and 26 patients with intrahepatic bile-duct carcinoma. Tn and STn antigens were expressed in most of the carcinomas, and were also often expressed in the atypical bile-duct epithelium of the patients with hepatolithiasis or carcinoma, whereas they were rarely or never expressed in the normal bile duct, suggesting that they are effective tumor markers. T antigen was less useful as a marker for intrahepatic bile-duct carcinoma or the atypical epithelium, because it was expressed in normal bile-duct of some cases. Regarding the expression of ARAs in the carcinomas, non-invasive bile-duct cyst adenocarcinomas with favorable prognosis either expressed no MUCI-ARA with [DF3(-), MUSEII(-) and 139H2(-)] staining pattern or expressed MUCI-ARA with [DF3(-), MUSEII(+) and 139H2(+)] staining pattern. However these tumors often expressed MUC2-ARA with [anti-MRP(+) and CCP58(+)] staining pattern. In contrast, most invasive non-papillary cholangiocarcinomas with poor prognosis expressed MUCI-ARA with [DF3(+), MUSEII(+) and 139H2(+)] staining pattern, but expressed no MUC2-ARA with [anti-MRP(-) and CCP58(-)] staining pattern. These results suggests that different apomucins are produced by bile-duct cystadenocarcinomas and cholangiocarcinomas with differing prognosis. Furthermore, expression of Tn and STn antigens is a useful indicator of malignancy in the intrahepatic duct.

Adenoma, Bile Duct↗
PubMed1993

Immune recognition of human colonic-tumour-associated MUC-2 mucins using an anti-peptide antibody.

In human intestinal malignancy, alterations occur in the expression of mucins defined by the MUC-2 gene. These changes include the unmasking of epitopes in the mucin protein core. In order to probe these modifications associated with mucins of the malignant phenotype, a monoclonal antibody (MAb) was developed against synthetic peptide with a sequence based upon that of the protein core of the MUC-2 mucin. The antibody (designated 996) was shown to recognize a high-molecular-weight glycoprotein from colonic carcinoma tissue. The material reacted uniformly with Concanavalin A but variably with other lectins, indicating heterogeneity in the associated oligosaccharide side chains. The protein core was accessible both to 996 antibody binding and to degradation with proteases. Immunization with the affinity-purified mucin-like material elicited antibodies reactive with both the immunogen and the synthetic peptides, confirming the immunogenic character of protein-core determinants. Epitope mapping studies, using synthetic peptides in solution and synthetic peptides tethered to the heads of plastic pins, indicated that the minimum epitope for the 996 antibody is a tetramer of T G T Q. Antibody interaction with the glutamine (Q) residue was determined to be of major importance in the antigen-antibody reaction. The findings illustrate the characterization of an anti-peptide antibody which may be used to probe alterations in MUC-2 mucin expression associated with human intestinal malignant disease.

Adsorption↗
PubMed1994

Expression of MUC1, MUC2, MUC3 and MUC4 mucin mRNAs in human pancreatic and intestinal tumor cell lines.

We examined the steady-state expression levels of mRNA for the MUC1, MUC2, MUC3 and MUC4 gene products in 12 pancreatic tumor cell lines, 6 colon tumor cell lines, and one ileocecal tumor cell line. The results showed that 10 of 12 pancreatic tumor cell lines expressed MUC1 mRNA and that 7 of these 12 lines also expressed relatively high levels of MUC4 mRNA. In contrast, MUC2 mRNA was expressed at only low levels and MUC3 was not detected in the pancreatic tumor cell lines. All 7 intestinal tumor cell lines examined expressed MUC2, and 5 of 7 expressed MUC3; however only one expressed significant levels of MUC1 and 2 expressed low levels of MUC4 mRNA. This report of high levels of MUC4 mRNA expression by pancreatic tumor cells raises the possibility that mucin carbohydrate epitopes defined by antibodies such as DuPan 2 may be expressed on a second mucin core protein produced by pancreatic tumor cells.

Base Sequence↗
PubMed1994

Expression of MUC2-mucin in colorectal adenomas and carcinomas of different histological types.

The expression of mucin MUC2 was investigated in normal colonic tissue, in colonic adenomas and in carcinomas of the mucinous and non-mucinous type. The latter were subdivided into carcinomas originating from the adenoma-carcinoma sequence (ACS) and de novo (DN) carcinomas. The expression was assayed by immunohistochemistry with the monoclonal anti-MUC2 antibody CCP58 and by mRNA semiquantitation. MUC2 protein epitope CCP58 was strongly expressed in 21% of normal colonic tissues, in 40% of villous and in 48% of tubular adenomas. Mucinous carcinomas exhibited strong expression in 72%, ACS carcinomas in 21% and DN adenocarcinomas in none of the tumors investigated. Compared with the adjacent non-malignant tissue (transitional mucosa), CCP58 epitope expression in the tumor was higher in 74% of mucinous carcinomas, but equal or lower in 69% of ACS carcinomas and in 100% of de novo carcinomas. The alterations of MUC2 expression detected by immunohistochemistry in adenocarcinomas were confirmed on mRNA level. These data indicate that the MUC2 expression pattern is different in the 3 carcinoma types investigated. MUC2 over-expression occurs in the adenomatous tissue. It is always maintained in mucinous carcinomas, but frequently decreased in non-mucinous ACS carcinomas. DN carcinomas are most frequently associated with decreased expression of MUC2.

Adenocarcinoma, Mucinous↗
PubMed1994

Molecular cloning of a cDNA coding for a region of an apoprotein from the 'insoluble' mucin complex of rat small intestine.

The major part of rat small intestinal mucins occurs as an 'insoluble' glycoprotein complex unextractable in 6 M guanidinium chloride unless disulfide bonds are cleaved. One of the trypsin-resistant high-glycosylated domains of this complex (glycopeptide A) was recently isolated. We have now deglycosylated it with HF, injected it into rabbits and the obtained antiserum was used for expression cloning providing a cDNA clone (VR-1A). This clone contained an open reading frame of 235 amino acids composed of two regions. The deduced N-terminal 53 amino acids included seven Cys residues and only one Ser, followed by a region of 182 residues with 64% Ser and Thr but devoid of Cys residues. Analysis of mRNA revealed a transcript of about 12 kb, identical in size to a band labelled with a probe based on the rat mucin-like protein (MLP/Muc2) cDNA. Pulsed-field gel electrophoresis of genomic rat DNA showed identical bands (380 and 500 kb) when blots were sequentially probed with the MLP/Muc2 probe and VR-1A. A panel of mouse x rat hybrids was used to localize the gene corresponding to both VR-1A and Muc2 to rat chromosome 1. The results strongly suggest that the 'insoluble' mucin complex of the rat small intestine is encoded by the Muc2 gene.

Amino Acid Sequence↗
PubMed1994

Alteration in expression of MUC2 and MUC3 mRNA levels in HT29 colonic carcinoma cells.

The cDNAs for two mucins, MUC2 and MUC3, have been derived from intestinal cells, however, the mechanisms that control expression of these genes are unknown. Steady-state mRNA levels for mucin gene products were examined in HT29 colonic carcinoma cells. Cells were grown in a conventional glucose medium and a glucose-free galactose medium to induce phenotypic differentiation. Northern blot analyses using cDNA probes of MUC2 and MUC3 were performed. MUC2 mRNA levels were decreased in cells grown in galactose medium compared to glucose medium whereas MUC3 mRNA levels were increased when cells were grown in galactose medium compared to those grown in galactose-free, glucose medium. This report shows steady state mucin gene expression is altered in HT29 cells grown in a medium that induces phenotypic differentiation and may provide a model for evaluation of induction of mucin gene expression.

Actins↗
PubMed1996

Quantitative analysis of MUC2 synthesis in ulcerative colitis.

MUC2 is the predominant mucin in the human colon responsible for the protective mucus layer. We developed methods to quantify MUC2 biosynthesis, which were used to study the regulation of MUC2 expression in the colon of normal individuals and of patients with ulcerative colitis. Colonic biopsies were metabolically labeled, and biosynthesis of MUC2 precursor was quantified using SDS-PAGE. Total MUC2 and MUC2 mRNA were quantified using blotting techniques. MUC2 precursor biosynthesis and total MUC2 levels were significantly decreased in ulcerative colitis patients with active inflammation compared to controls. In contrast, both these parameters returned to control values during remission of the inflammation, demonstrating that colonic biosynthesis and total amounts of MUC2 vary according to the activity of the disease. However, MUC2 mRNA levels were similar in all patients and independent of disease activity, indicating that these variations in MUC2 synthesis are post-transcriptionally regulated.

Biomarkers, Tumor↗
PubMed1996

Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes.

Four distinct genes that encode mucins have previously been mapped to chromosome 11p15.5. Three of these genes (MUC2, MUC5AC, and MUC6) show a high level of genetically determined polymorphism and were analyzed in the CEPH families. Linkage analysis placed all three genes on the genetic map in a cluster between HRAS and INS, and more detailed analysis of recombinant breakpoints revealed that MUC6 is telomeric to MUC2. Using these recombinants D11S150 was mapped close to MUC2. Ten of the 11 recombinant chromosomes studied in detail were paternal, and the recombinant events were distributed throughout the 11p15 region, suggesting that the high level of recombination observed in 11p15.5 is not due to a particular recombinational hot spot. Pulsed-field gel electrophoresis was used to make a detailed physical map of the MUC cluster and to integrate the physical and genetical maps. The gene order was determined to be HRAS-MUC6-MUC2-MUC5AC-MUC5B-IGF2. The MUC genes span a region of some 400 kb and the map extends 770 kb and contains 15 putative CpG islands. The order of the MUC genes on the map corresponds to the relative order of their expression along the anterior-posterior axis of the body, suggesting a possible functional significance to the gene order.

Adult↗
PubMed1996

Aspirin changes the secretion rate and amino acid composition of human small intestinal mucin in subjects with ileal conduits.

The effect of aspirin on the rate of secretion and amino acid composition of human ileal mucin was studied, using subjects with ileal conduits as a model system in which mucin secreted from the ileal conduit tissue is flushed out in the urine and can be measured and analysed. Aspirin (600 mg per day, administered orally) increased the daily mucin output by 37-104% in subjects by days 3 or 4, but thereafter the mucin output declined to below the baseline level by day 10. Mucin samples, purified from the ileal conduit urine during the control period and during aspirin administration, were compared. There were no discernible changes in the degree of polymerisation or the density, but during aspirin administration the amino acid composition was significantly changed, and in particular threonine and proline were enriched. One possible explanation, consistent with the compositional analyses, is that the N- and C-terminal regions of the mucin subunits have been cleaved off and lost during aspirin administration. The observed changes in mucin secretion may have implications for the mechanism of the toxic effects of aspirin on the small intestine by altering the barrier properties of the mucus layer.

Amino Acids↗
PubMed1996

Colonic mucins in ulcerative colitis: evidence for loss of sulfation.

Colonic tissue obtained at surgery from control individuals and patients with ulcerative colitis was used to isolate mucins and to prepare mucin glycopolypeptides by pronase digestion. These were compared with mucins labelled with [35S] sulfate and [3H]-glucosamine after organ culture tissue samples from the same patients. A significant loss of mucin sulfation was detected in the colitis patients by both metabolic labelling and chemical analysis of the glycopolypeptides. A change in the size distribution of purified mucin oligosaccharides fractionated on BioGel P6 after release by beta-elimination was seen in both radiolabelled and non-labelled colitis mucins compared with controls. Amino acid analysis of the glycopolypeptides showed a close similarity to the expected ratio of serine:threonine:proline for MUC2 and did not vary between control and colitis groups. Analysis of the mucins confirmed > 90% purity in the labelling experiments, characteristic behaviour on density gradient centrifugation and agarose gel electrophoresis in control and ulcerative colitis groups and differences in sulfation and turnover at various sites in the normal colon.

Amino Acids↗
PubMed1996

Molecular characterization of the large heavily glycosylated domain glycopeptide from the rat small intestinal Muc2 mucin.

The largest high-glycosylated domain, glycopeptide A, of the "insoluble' mucin complex of the rat small intestine has earlier been purified and characterized (Carlstedt et al., 1993, J Biol Chem 268: 18771-81). A rabbit antiserum raised against deglycosylated glycopeptide A was used to clone part of a mucin showing homology to the human MUC2 mucin (Hansson et al., 1994, Biochem Biophys Res Commun 198. 181-90). This serum specifically stained goblet cells (paranuclear) in the mouse small intestine. The size of the coding sequence of glycopeptide A was estimated by using reversed transcriptase PCR of mRNA from an inbred rat strain (GOT-W) using primers in the unique central and C-terminal parts of the proposed rat Muc2 sequences. The PCR and Southern blot of the PCR products showed a fragment of about 5.5 kb corresponding to about 1700 amino acids when the known Cys-rich sequences used for the primers were subtracted. This is slightly larger than the size estimated earlier by biochemical studies. The mRNA encoding the rat Muc2 was slightly smaller than the mRNA encoding the human MUC2 in a colorectal cell line. Although the size of glycopeptide A estimated from biochemical results and by PCR is not identical, the results obtained here further support that the "insoluble' mucin of the rat small intestine is encoded by the Muc2 gene. Most of the oligosaccharides in glycopeptide A were either neutral (40%) or sialylated (40%). The remaining ones were sulfated with the sulfate group attached to C-6 of N-acetylglucosamine linked to C-6 of the N-acetylgalactosaminitol as revealed by tandem mass spectrometry of the perdeuteroacetylated oligosaccharides. Eighteen oligosaccharides were found of which fourteen were characterized and found to be mostly novel. Our findings thus expand the current knowledge of the core peptide of the rat intestinal goblet cell mucin and provide a relatively complete picture of the glycosylation of a defined mucin domain.

Animals↗
PubMed1996

The transcripts of the apomucin genes MUC2, MUC4, and MUC5AC are large and appear as distinct bands.

RNA from four colorectal carcinoma cell lines was prepared and analysed in Northern blots using probes for the MUC2, MUC4, and MUC5AC mucin apoprotein genes. The sizes of the transcripts were very large, in the order of at least 12-16 kb. The presence of distinct bands is in contrast to earlier reports, where these transcripts showed extensive polydispersity. RNA from rat small intestine was also prepared and probed with cDNA for the rat Muc2 mucin gene. This analysis also showed a large and discrete hybridizing band, indicating that apomucin mRNA of well-defined size can be obtained also from a tissue with high endogenous RNase activity.

Animals↗
PubMed1996

MUC5AC, but not MUC2, is a prominent mucin in respiratory secretions.

Airway mucus was collected from healthy and chronic bronchitic subjects. The chronic bronchitic sputum was separated into gel and sol phase by centrifugation and mucins were isolated using isopycnic density-gradient centrifugation in CsCl. The presence of the MUC5AC and MUC2 mucins was investigated with antisera raised against synthetic peptides with sequences from the respective apoproteins. The gel and sol phase of chronic bronchitic sputum as well as healthy respiratory secretions were shown to contain MUC5AC whereas the MUC2 mucin could not be detected. Rate-zonal centrifugation showed that the MUC5AC mucin was large, polydisperse in size and that reduction yielded subunits. Ion-exchange HPLC revealed the presence of two subunit populations in all secretions, the MUC5AC subunits always being the more acidic. MUC5AC is thus the first large, subunit-based, gel-forming respiratory mucin identified and this glycoprotein is biochemically distinct from at least one other population of large, gel-forming mucins also composed of subunits but lacking a genetic identity.

Bronchitis↗