Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the core blood group structures sialosyl Tn (STn) and Tn is regarded as a colorectal cancer-specific change reflecting truncated synthesis of the oligosaccharide component of goblet cell mucin. The distribution of STn and Tn in normal and malignant epithelium has been studied in detail by a combination of mucin-, lectin-, and immunohistochemistry with and without pretreatment with potassium hydroxide (KOH), neuraminidase, and KOH-neuraminidase. When O-acetylated sialic acid (neuraminidase-resistant) is converted by saponification to non-O-acetylated sialic acid (neuraminidase-sensitive), normal colorectal goblet cells (mainly of the lower two-thirds of crypts) are immunoreactive with the monoclonal antibody TKH2 (specific for STn). This immunoreactivity is abolished by the interposition of neuraminidase, but goblet cells then become immunoreactive with Hb-Tn1 (specific for Tn). While colorectal cancer mucin expresses STn, expression of Tn is not seen in either goblet cell mucin or extracellular material showing the morphological and histochemical characteristics of secretory mucin. Tn expression in cancers is mainly limited to the Golgi zone and in a proportion of cases to cytoplasm and apical membrane (glycocalyx) of columnar cells and inspissated material within lumina. The material reacting with Hb-Tn1 may be upregulated, membrane-associated MUC1 glycoprotein rather than MUC2 or MUC4 goblet cell mucin. The presence of STn and cryptic Tn within normal colorectal goblet cells and the absence of Tn expression within colorectal cancer secretory mucin contradicts the generally accepted concept of cancer-specific incomplete glycoprotein synthesis within these neoplasms.
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PMID:Distribution of sialosyl Tn and Tn antigens within normal and malignant colorectal epithelium. 763 24

The human MUC2 gene maps to chromosome 11p15, where three additional mucin genes have been located, and encodes the most abundant gastrointestinal mucin normally expressed in the intestinal goblet cell lineage. However, in pathological conditions, including colorectal cancer, MUC2 can be abnormally expressed. Therefore, it is of considerable interest to understand the regulation of the MUC2 gene and how the mechanism is altered in colon cancer. Toward this goal, we have isolated a group of overlapping clones (contig) spanning 85 kilobases harboring the entire MUC2 locus, including sequences located upstream of the gene. Detection of two DNase I-hypersensitive sites in the 5' region of the MUC2 gene suggests the presence of DNA regulatory elements. To better characterize this region, we have sequenced 12 kilobases of the upstream region and analyzed it for functional activity by cloning portions of it into a luciferase reporter vector and assaying for promoter/enhancer activity using a transient transfection assay. A fragment from the AUG translational initiation codon +1 to -848 confers maximal transcriptional activity in several intestinal cell lines. Elements located further upstream exert a negative effect on the expression of the reporter gene when tested in conjunction with homologous or heterologous promoters. The same pattern of expression is observed when the MUC2/luciferase constructs are transfected into HeLa cells, which do not express the endogenous MUC2 gene. However, the level of activity in HeLa cells is at least an order of magnitude higher, suggesting that additional sequences singularly or in combination are responsible for the tissue- and cell lineage-specific expression of MUC2. Finally, we have identified an additional mucin-like gene (MUCX), located upstream of MUC2. We show that this MUCX gene, that is transcribed in opposite orientation to that of MUC2, is expressed with a pattern distinct from that of MUC2, yet similar to that of MUC5B and MUC6, two additional mucin genes located at chromosome 11p15. Recent information on the order of the mucin genes at chromosome 11p15 suggests that MUCX may be MUC6, one of the already identified mucin genes, or a novel one, yet to be fully characterized.
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PMID:Organization and regulatory aspects of the human intestinal mucin gene (MUC2) locus. 906 67

Luminal secretions within colorectal cancers have been assumed to be the counterpart of normal goblet cell mucin. The aim of this study was to establish whether secretory material within colorectal cancers may in fact be traced to different lineages: goblet cells and columnar cells. The distribution of the apomucins MUC1 and MUC2, non-O-acetylated sialic acid and the carbohydrate structures sialosyl Tn, Tn, Lewis(x), sialosyl Lewis(x) and Lewis(y) was studied in normal colorectal mucosa and colorectal cancer specimens using standard histochemical techniques. Unmasking of MUC1 and MUC2 was achieved using periodic acid and saponification-neuraminidase-periodic acid pretreatment respectively. Within normal and malignant epithelium, correlations and/or co-localization could be demonstrated for goblet cells with MUC2, non-O-acetylated sialic acid, sialosyl Tn, Tn (Golgi region) and sialosyl Lewis(x), and for columnar cells with MUC1, Lewis(x), sialosyl Le(x), Tn (cytoplasm) and Lewis(y) (UEA-1). The goblet cell spectrum was associated with mucin-like (type I) luminal secretions within cancers, whereas the columnar cell spectrum characterized non-mucin-like (type II) secretions and intracytoplasmic lumina. These data indicate that colorectal cancer mucin can be broadly separated into two types: secretory mucin linked to cells of goblet lineage and up-regulated membrane-associated mucin of presumed columnar cell origin.
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PMID:Correlative histochemical study providing evidence for the dual nature of human colorectal cancer mucin. 914 71

A synthetic peptide corresponding to the human MUC2 tandem repeat domain containing 14 Thr residues was glycosylated in vitro using UDP-GalNAc and microsomal membranes of the colorectal cancer cell line, LS180. The products were fractionated by reverse phase HPLC, which gave seven glycopeptide fractions. Their molecular weights were estimated by matrix-assisted laser desorption/ionization mass spectrometry, the values obtained corresponding to glycopeptides containing from one to ten GalNAc residues. On solid phase radioimmunoassaying involving a monoclonal anti-Tn antibody (MLS128), it was found that the glycopeptides containing nine or ten GalNAc residues were strongly immunoreactive, whereas the glycopeptides containing less than six GalNAc residues were inactive, indicating that a cluster of GalNAc-Thr is essential for the Tn antigenicity.
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PMID:Glycosylation of the tandem repeat unit of the MUC2 polypeptide leading to the synthesis of the Tn antigen. 953 76

Hyperplastic polyps and serrated adenomas of the colorectum show mixed gastrointestinal differentiation, expressing both gastric (M1 or MUC5AC) and intestinal (MUC2) mucins. They also share the phenotype of mild DNA microsatellite instability (MSI-L). Recent findings of clonal genetic changes within hyperplastic polyps fit with a pathway of serrated neoplasia, perhaps culminating in the subset of colorectal cancer characterized by the mild mutator phenotype.
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PMID:Serrated adenoma and colorectal cancer. 1039 14

Seven (3.3%) of 213 patients who underwent surgery for early colorectal cancer (invasion limited to no deeper than the submucosa) at the National Cancer Center Hospital, Tokyo, between 1986 and 1995 had synchronous (2 patients) or metachronous (5 patients) liver metastases. The average period from surgical resection of the primary colorectal cancer to the diagnosis of liver metastases was 25 months (range, 0-52 months). The clinicopathologic and immunohistochemical features of the primary lesions in these patients were compared with these features in the lesions in consecutive patients with early colorectal cancer who had no evidence of liver metastases within at least 5 years after colorectal resection. Venous invasion was more frequent in the primary lesions with liver metastases than in those without liver metastases (57% vs 0%; P = 0.0035). Expression of p53 and CD44v9 was more frequent in the primary lesions with liver metastases (71% and 100%) than in those without metastases (56% and 72%). In contrast, MUC2 expression was more frequent in the primary lesions without liver metastases (72%) than in those with metastases (43%). Venous invasion is considered to be closely related to liver metastasis, and the immunohistochemical expression of p53 and CD44v9 provides useful information for identifying those patients with early colorectal cancer who have a high risk of developing liver metastases.
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PMID:Clinicopathologic and immunohistochemical study of early colorectal cancer with liver metastases. 1043 8

Poor survival in patients following resection for early stage colorectal cancer is thought to be due in part to the presence of occult micrometastases at the time of surgery. The MUC2 mucin gene is highly expressed in the colon and associated colorectal tumors and may be a candidate marker for colorectal cancer micrometastases. We have used RT-PCR to detect expression of MUC2 mRNA transcripts in order to identify possible lymph node micrometastases in node negative (Stage I and II, or Dukes A and B) colorectal cancer patients. A total of 396 nodes (histologic stage N0) from 34 colon and nine rectal cancers were studied by RT-PCR analysis with nested primers for MUC2 (an average of 7.6 nodes per case). In the primary tumors, 42/43 (98.1%) were positive for MUC2 by RT-PCR. Evidence of the presence of MUC2 was demonstrated in nodes from 0 of 10 (0%) patients with Tis or T1, one of six (16.7%) from T2, 10 of 25 (40.0%) from T3, and one of two (50%) from T4 tumors. MUC2 RT-PCR was negative in six nodes from three patients with non-malignant colon disease and positive in histologically positive lymph nodes from six of six (100%) stage III colon cancers. In this study, using RT-PCR to detect the presence of MUC2 transcripts, we have found preliminary evidence for possible micrometastatic disease in approximately a third of histologically negative N0 colorectal cancer patients. The increased presence of MUC2 expression also correlated with more advanced T stage. We conclude that MUC2 RT-PCR may be a sensitive and specific marker for occult micrometastases. This technique has the potential to identify a group of colorectal cancer patients at risk for early cancer recurrence.
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PMID:Evidence for colorectal cancer micrometastases using reverse transcriptase-polymerase chain reaction analysis of MUC2 in lymph nodes. 1075 25

Altered expression of mucin gene products has been described in many epithelial cancers including colorectal cancer. However, mucins are heavily O-glycosylated making the study of apomucin expression difficult. In this study, we describe a novel method of chemical deglycosylation of mucin gene products on paraffin embedded formalin-fixed tissue sections. In the normal and cancerous colorectum, our results suggest that alkali-catalyzed beta-elimination of periodate oxidized glycan method of chemical deglycosylation modifies the structure of carbohydrates sensitive to mild periodate oxidation resulting in less steric hindrance and selectively removes Tn and sialyl-Tn structures, partially exposing the underlying apomucin epitopes. Using this method, we have demonstrated that the MUC1 tandem repeat epitope recognized by MAb 139H2 is masked predominantly due to steric hindrance by carbohydrate structures whereas the MUC2 tandem repeat epitope recognized by MAb CCP58 and pAb MRP and the MUC3 tandem repeat epitope recognized by pAb M3P are masked by the presence of carbohydrate side chains O-linked to Ser/Thr residues within the epitope. Considerable differences in the level and pattern of expression of the epitopes in the tandem repeat region of apomucins of MUC1, MUC2, and MUC3 were observed between normal and cancerous colorectal cancer tissues. We conclude that this novel chemical deglycosylation method that causes selective cleavage of distinct glycans will be useful in unmasking various mucin gene products and glycoproteins containing similar O-glycosidic linkages in the tissue sections of formalin-fixed paraffin embedded normal and pathological tissues.
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PMID:Alkali-catalyzed beta-elimination of periodate-oxidized glycans: a novel method of chemical deglycosylation of mucin gene products in paraffin embedded sections. 1142 89

Sialyl-Tn (STn), a mucin-associated disaccharide antigen carried by apomucins such as MUC2, plays an important role in tumor biology. However, little is known about the subcellular localization and compartments involved in STn synthesis. In this study we used immunoelectron microscopy to localize STn and MUC2 apomucin in human colorectal tissues. MUC2 apomucin was localized predominantly in the rough endoplasmic reticulum (RER) in normal colorectal mucosa (n=6), colorectal adenoma (n=8), and colorectal adenocarcinoma (n=10). STn, recognized by monoclonal antibody TKH2, was not readily detectable in normal colorectal mucosa but becomes manifest in both trans-Golgi apparatus and mucin droplets in colorectal adenoma. In colorectal adenocarcinoma, STn was localized not only in late but also in early Golgi compartments, and particularly in some RER lumens. Furthermore, electron microscopic in situ hybridization revealed that gold particles representing MUC2 mRNA are primarily localized over the RER. Our findings indicate that in colorectal adenoma STn sialylation takes place in the trans-Golgi apparatus, whereas in colorectal cancer STn sialylation occurs in all the Golgi compartments and in the RER.
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PMID:Altered GalNAc-alpha-2,6-sialylation compartments for mucin-associated sialyl-Tn antigen in colorectal adenoma and adenocarcinoma. 1172 6

MUC2 is a secretory mucin normally expressed by goblet cells of the intestinal epithelium. It is overexpressed in mucinous type colorectal cancers but down-regulated in colorectal adenocarcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment of colon cancer cell lines increases MUC2 expression, so we have undertaken a detailed analysis of the effects of PMA on the promoter activity of the 5'-flanking region of the MUC2 gene using stably and transiently transfected promoter reporter vectors. Protein kinase C inhibitors (bisindolylmaleimide, calphostin C) and inhibitors of mitogen-activated protein/extracellular signal regulated kinase kinase (MEK) (PD98059 and U0126) suppressed up-regulation of MUC2. Src tyrosine kinase inhibitor PP2, a protein kinase A inhibitor (KT5720), and a p38 inhibitor (SB 203580) did not affect transcription. Western blotting and reverse transcription-PCR analysis confirmed these results. In addition, co-transfections with mutants of Ras, Raf, and MEK showed that the induction of MUC2 promoter activity by PMA required these three signaling proteins. Our results demonstrate that PMA activates protein kinase C, stimulating MAP kinase through a Ras- and Raf-dependent mechanism. An important role for nuclear factor kappaB (NF-kappaB) was also demonstrated using the inhibitor caffeic acid phenethyl ester and electrophoretic mobility shift assays. Such identification of pathways involved in MUC2 up-regulation by PMA in the HM3 colon cancer cell line may serve as a model for the effects of cytokines and growth factors, which regulate MUC2 expression during the progression of colorectal cancer.
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PMID:Phorbol 12-myristate 13-acetate up-regulates the transcription of MUC2 intestinal mucin via Ras, ERK, and NF-kappa B. 1207 18


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