Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of blood group ABH antigens is under genetic control, where the primary gene products are glycosyltransferases. Several studies have demonstrated cancer-associated alterations in ABH antigen expression in human colon cancer tissues. However, the mechanism(s) responsible for these alterations has not been elucidated. Therefore, experiments were conducted using nine established colon cancer cell lines (four type O, three type A, and two type B) to examine ABH antigen expression by immunocytochemistry and correlate this with activities of ABH biosynthetic (glycosyltransferase) and degradative (glycosidase) enzymes. The products of the glycosyltransferase enzymes were characterized by high performance liquid chromatography and paper chromatography, and substrate affinities (apparent Km values) of the cancer cell-derived glycosyltransferases were analyzed. The present data demonstrate: (a) all cell lines except H-498 (blood type A) expressed the appropriate ABH glycosyltransferase as well as all three glycosidases; (b) product characterization and substrate dependence experiments suggested that the cancer cell-derived ABH glycosyltransferase enzymes had properties that were similar to those of the ABH enzymes in human serum; (c) H-498 cells exhibited A antigen deletion with accumulation of H precursor substance, most likely due to insufficient A transferase activity; (d) SW1417 cells (blood type B) demonstrated B antigen deletion without precursor accumulation, despite adequate levels of B transferase and low alpha-galactosidase activity; and (e) weak incompatible A antigen expression occurred in LoVo (type B) and SW1116 (type O) cells, and weak incompatible B antigen expression occurred in H-498 (type A) and SW1116 cells. However, since these cells lacked incompatible A or B transferase activity, these incompatible antigens are probably not the true A or B antigens. Thus, the colon cancer cell lines used in this study exhibit all of the ABH alterations previously described in colon cancer tissues and appear to be useful experimental models for studying the molecular events involved in cancer-associated ABH expression.
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PMID:ABH blood group antigen expression, synthesis, and degradation in human colonic adenocarcinoma cell lines. 254 45

Several alterations in carbohydrate antigen expression can occur in colon cancers. Modified structures such as extended LeX and LeY antigens could serve as cancer-associated antigens in the human colon, although none is specific only for colon cancer. Since LeX and LeY antigens are present in fetal tissues, but not in adult normal tissues, these antigens appear to be oncodevelopmental in nature. The expression in colon cancers of extended LeX and LeY antigens with internal fucosylation or terminal sialylation is considered rather cancer-specific since normal colonic mucosa does not express these antigens. Furthermore, these molecules may also be "markers" for premalignancy, since adenomatous polyps, but not hyperplastic polyps are capable of exhibiting these changes and antigenic expression often correlates with malignant potential in adenomatous polyps. The precise biochemical and molecular mechanisms for these alterations in LeX and LeY expression and their biological significance are not well understood at the present time. However, it is likely that the regulation of the glycosyltransferase enzymes responsible for the processes of polylactosamine elongation, fucosylation, and sialylation may be aberrant. Obviously further studies are needed to elucidate these mechanisms. However, it appears that the monoclonal antibodies directed against extended LeX and LeY antigens are a useful adjunct in the diagnosis of colonic neoplasia, and may also be helpful in elucidating the molecular and biochemical mechanisms involved in the adenoma-carcinoma sequence.
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PMID:Carbohydrate antigen expression in the adenoma-carcinoma sequence. 305 24

UDP-GlcNAc: GalNAc-R beta 3-GlcNAc-transferase (core 3 beta 3-GlcNAc-T, where GlcNAc is N-acetyl-D-glucosamine, GalNAc is N-acetyl-D-galactosamine and T is transferase) is expressed in a tissue-specific fashion and is high in normal colonic tissue, but downregulated in colon cancer. To further study the control of this enzyme, we examined the activity in pig, rat and human colonic tissues, and several human cancer cell lines. The enzyme was difficult to solubilize by detergents and was extremely unstable in the solubilized form. Using synthetic derivatives of the GalNAc-R substrate, we showed that the specificity of the enzyme in normal rat and human colonic mucosa requires all the substituents of the GalNAc-sugar ring of substrates for maximal activity. Core 3 beta 3-GlcNAc-T was significantly influenced by the structure of the aglycon group. None of the inactive substrate derivatives could inhibit the activity. N-Iodoacetamido-galactosamine alpha-benzyl was a weak substrate and significantly inhibited the incorporation of GLcNAc into GalNAc alpha-benzyl by human colonic homogenates. Surprisingly, none of the colonic cancer cell lines or any other cancer and leukaemia cells examined exhibited detectable activity of the enzyme, although a number of other glycosyltransferase activities involved in O-glycan biosynthesis were active. Mixing experiments did not reveal an endogenous inhibitor in HL60 cells or an activator of core 3 beta 3-GlcNAc-T in human colonic mucosa. Thus, the lack of core 3 beta 3-GlcNAc-T in human colonic mucosa. Thus, the lack of core 3 beta 3-GlcNAc-T activity in cancer cell lines may be due to cell transformation or cell culturing.
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PMID:Synthesis of O-glycan core 3: characterization of UDP-GlcNAc: GalNAc-R beta 3-N-acetyl-glucosaminyltransferase activity from colonic mucosal tissues and lack of the activity in human cancer cell lines. 765 72

Human colon cancer is associated with antigenic and structural changes in mucin-type carbohydrate chains (O-glycans). To elucidate the control of the biosynthesis of these O-glycans is colon cancer, we have studied glycosyltransferase and sulphotransferase activities involved in the assembly of elongated O-glycan structures. We analysed homogenates prepared from cancer tissue, adjacent normal and distal normal tissue from 20 patients. Several transferase activities showed pronounced changes in cancer tissue. The changes correlate with previous findings of a loss of O-glycans in cancer mucins, but did not always correlate with levels of Tn, sialyl-Tn, T and Lex antigens in homogenates or with the differentiation status and Duke's stages of the cancer tissue or the patient's blood type, sex and age. UDP-GlcNAc: Gal NAc-R beta 3-N-acetylglucosaminyltransferase (where GlcNAc is N-acetyl-D-glucosamine and GalNAc is N-acetyl-D-galactosamine) synthesizing O-glycan core 3, GlcNAc beta 1-3GalNAc-, CMP-sialic acid: GalNAc-peptide alpha 6-sialyltransferase synthesizing the sialyl-Tn antigen and sulphotransferase activities towards O-glycan core 1, Gal beta 1-3GalNAc-, were found to be decreased in cancer. UDP-GlcNAc: Gal beta 1-3GalNAc beta 6-N-acetylglucosaminyltransferase was also decreased in cancer concomitant with a loss of the ability to synthesize the I antigen and core 4, GlcNAc beta 1-6(GlcNAc beta 1-3) GalNAc-, CMP-sialic acid: Gal beta 1-3GalNAc-R alpha 3-sialyltransferase and GDP-fucose: Gal beta-R alpha 2-fucosyltransferase, synthesizing the blood group H determinant, were found to be 4- and 3- to 8-fold increased, respectively, in cancer compared to normal tissue. The data suggest that the biosynthesis of antigens and mucin-bound O-glycan structures in colon cancer is subject to complex control mechanisms.
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PMID:Alterations of O-glycan biosynthesis in human colon cancer tissues. 773 50

Human colorectal cancers express various cancer-associated carbohydrate determinants such as Lewis Y or sialyl Lewis A, suggesting a considerable alteration in glycosyltransferase activities occurring upon malignant transformation. We investigated the mRNA amounts of fucosyltransferase (Fuc-T) and sialyltransferase (ST) isoenzymes, including Fuc-T III, IV, V, VI and VII and ST-3N, ST-30 and ST-4, in human colorectal cancer tissues by Northern blotting and RT-PCR. Regarding fucosyltransferases, mRNA of Fuc-T III and VI was not significantly altered, and only Fuc-T IV mRNA showed a moderate increase in cancer tissues when compared with adjacent non-malignant colonic epithelia taken from the same patient (273 +/- 96%; p < 0.001). The moderate increase of Fuc-T IV message may be related to an enhanced expression of Lewis Y in colon cancer tissues. In the ST isoenzymes, mRNA for ST-3N remained unchanged, whereas that for ST-4 decreased significantly in cancer tissues, to 32 +/- 29%, (p < 0.005). The most remarkable finding was that the message of ST-30 was prominently increased in cancer tissues compared with non-malignant colorectal mucosa. When further investigated by quantitative RT-PCR assays on a larger series of patients with colorectal cancers, the average increase in mRNA for ST-30 was 459 +/- 200% compared with that in adjacent non-malignant epithelium (significant at p < 0.0001). The increase of ST-30 message was more prominent in the cancer tissues strongly expressing sialyl Lewis A than in the cancer tissues expressing sialyl Lewis A only weakly or moderately (significant at p < 0.05). The marked increase in the message of ST-30 is suggested to be related to an enhanced expression of sialylated carbohydrate determinants in colon cancer tissues including sialyl Lewis A, since the enzyme exhibited a significant activity against the type 1 chain carbohydrate substrate and produced the precursors for sialyl Lewis A synthesis, when its cDNA was expressed in Cos-7 cells.
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PMID:Altered mRNA expression of specific molecular species of fucosyl- and sialyl-transferases in human colorectal cancer tissues. 917 8

The carbohydrate structures of glycoconjugates of cancer cells change markedly in comparison with those of noncancerous cells. We aimed to determine which glycosyltransferases are up-regulated or down-regulated in human colon cancer tissues in order for the dramatic change in carbohydrate structures to occur. The transcript levels of 12 glycosyltransferase genes were measured by a competitive reverse-transcription-PCR method in noncancerous and cancerous colorectal tissues. Eight well- to moderately differentiated and three poorly differentiated carcinomas were examined in comparison with noncancerous colon epithelial tissues adjacent to the carcinoma tissues. Two of the twelve glycosyltransferase genes, Fuc-TIV and ST3Gal II, were significantly up-regulated in all cancerous tissues regardless of the histologic features. Four genes, ST3Gal I, ST6Gal I, beta1,4GalT, and Core2 GnT, showed a tendency toward up-regulation, and a ST3Gal III gene showed a tendency toward down-regulation. The other genes, Fuc-TIII, Fuc-TVI, and ST3Gal IV, which were most abundantly expressed in colorectal tissues, did not show significant up-regulation except in the poorly differentiated carcinomas. The Fuc-TVII gene was expressed at a very low level and was not up-regulated, and the Fuc-TV gene was not expressed at all in the colorectal tissues. Interestingly, all of the 12 glycosyltransferase genes examined, except the Fuc-TV, Fuc-TVI, Fuc-TVII, and ST3Gal III genes, were markedly up-regulated in all of the poorly differentiated carcinomas. We concluded that multiple glycosyltransferase genes are up-regulated, probably leading to extensive glycosylation of glycoconjugates in colorectal cancer cells. Lastly, sialyl Lewis antigens, ie, sialyl Lewis x and a antigens, which are terminal epitopes of sugar chains and well known as tumor-associated antigens, were quantified by Western blotting analysis. Based on the levels of transcripts of the 12 enzymes together with the amounts of sialyl Lewis antigens, we concluded that Fuc-TIII, Fuc-TVI, and ST3Gal IV are mainly responsible for synthesis of the sialyl Lewis antigens in colon tissues, but are not responsible for the augmented expression of the antigens in colorectal cancers. The amounts of sialyl Lewis x and a epitopes on mucins in colon cancer tissues can thus be determined through combinatorial up-regulation of the multiple glycosyltransferase genes.
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PMID:Up-regulation of a set of glycosyltransferase genes in human colorectal cancer. 969 May 58

Cyclooxygenase-2 (COX-2) was recently reported (M. Tsujii and R. N. DuBois, Cell, 83: 493-501, 1995) to affect the metastatic potential of cells. Previous studies (M. Fukuda, Cancer Res., 56: 2237-2244, 1996) indicated that sialyl Lewis antigen expression is correlated with hematogenous metastasis of colon cancer. In the present study, we investigated the interaction between COX-2 activity, expression of sialyl Lewis antigens, in vitro cancer cell adhesion to endothelial cells, and in vivo metastatic potential. Effects of COX-2 activity and prostaglandin E(2) on cell adhesion, expression of sialyl Lewis antigens, and glycosyltransferase genes were determined in Caco-2-m (COX-2 low level), Caco-2-COX-2 (programmed to overexpress COX-2), and HT-29 (COX-2 high level) cells. Metastatic spread of these cells to the liver was also investigated. Caco-2-COX-2 cells had increased SPan-1 levels and increased adherence to endothelial cells via SPan-1 compared with Caco-2-m cells. HT-29 cells expressed sialyl Lewis a and adhered to endothelial cells via sialyl Lewis a. Treatment with a COX-2 inhibitor, celecoxib, decreased SPan-1 and sialyl Lewis a expression and adherence to endothelial cells. beta 3Gal-T5 and ST3Gal III and IV expression was inhibited by celecoxib and was enhanced by prostaglandin E(2) treatment. Caco-2-COX-2 and HT-29 cells metastasized to the liver, whereas Caco-2-m cells did not. Pretreatment with celecoxib reduced the metastatic potential as well as anti-sialyl Lewis antibodies. Our results indicate a direct link between COX-2 and enhanced adhesion of carcinoma cells to endothelial cells, and enhanced liver metastatic potential via accelerated production of sialyl Lewis antigens. COX-2 inhibitors may suppress metastasis.
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PMID:Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis. 1188 37

Ulcerative colitis and Crohn's disease (together known as Inflammatory Bowel Disease or IBD) are both associated with increased risk for colorectal cancer. Although it is conventional to emphasise differences between IBD-associated and sporadic colon cancer, such as a lower rate of Adenomatosis Polyposis Coli mutations and earlier p53 mutations, IBD-associated cancer has a similar dysplasia-cancer sequence to sporadic colon cancer, similar frequencies of major chromosomal abnormalities and of microsatellite instability and similar glycosylation changes. This suggests that IBD-associated colon cancer and sporadic colon cancer might have similar pathogenic mechanisms. Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to suggest that both IBD-associated and sporadic colon cancer may be the consequence of bacteria-induced inflammation. We have speculated that the glycosylation changes might result in recruitment to the mucosa of bacterial and dietary lectins that might otherwise pass harmlessly though the gut lumen. These could then lead to increased inflammation and/or proliferation and thence to ulceration or cancer. The glycosylation changes include increased expression of onco-fetal carbohydrates, such as the galactose-terminated Thomsen-Friedenreich antigen (Gal beta1,3GalNAc alpha-), increased sialylation of terminal structures and reduced sulphation. These changes cannot readily be explained by alterations in glycosyltransferase activity but similar changes can be induced in vitro by alkalinisation of the Golgi lumen. Consequences of these changes may be relevant not only for cell-surface glycoconjugates but also for intracellular glycoconjugates.
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PMID:Altered glycosylation in inflammatory bowel disease: a possible role in cancer development. 1282 Jul 18

The type 1 carbohydrate chain, Galbeta1-3GlcNAc, is synthesized by UDP-galactose:beta-N-acetylglucosamine beta1,3-galactosyltransferase (beta3Gal-T). Among six beta3Gal-Ts cloned to date, beta3Gal-T5 is an essential enzyme for the synthesis of type 1 chain in epithelium of digestive tracts or pancreatic tissue. It forms the type 1 structure on glycoproteins produced from such tissues. In the present study, we found that the transcriptional regulation of the beta3Gal-T5 gene is controlled by homeoproteins, i.e. members of caudal-related homeobox protein (Cdx) and hepatocyte nuclear factor (HNF) families. We found an important region (-151 to -121 from the transcription initiation site), named the beta3Gal-T5 control element (GCE), for the promoter activity. GCE contained the consensus sequences for members of the Cdx and HNF families. Mutations introduced into this sequence abolished the transcriptional activity. Four factors, Cdx1, Cdx2, HNF1alpha, and HNF1beta, could bind to GCE and transcriptionally activate the beta3Gal-T5 gene. Transcriptional regulation of the beta3Gal-T5 gene was consistent with that of members of the Cdx and HNF1 families in two in vivo systems. 1) During in vitro differentiation of Caco-2 cells, transcriptional up-regulation of beta3Gal-T5 was observed in correlation with the increase in transcripts for Cdx2 and HNF1alpha. 2) Both transcript and protein levels of beta3Gal-T5 were determined to be significantly reduced in colon cancer. This down-regulation was correlated with the decrease of Cdx1 and HNF1beta expression in cancer tissue. This is the first finding that a glycosyltransferase gene is transcriptionally regulated under the control of homeoproteins in a tissue-specific manner. beta3Gal-T5, controlled by the intestinal homeoproteins, may play an important role in the specific function of intestinal cells by modifying the carbohydrate structure of glycoproteins.
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PMID:Lewis type 1 antigen synthase (beta3Gal-T5) is transcriptionally regulated by homeoproteins. 1285 3

The Sd(a) antigen is a carbohydrate determinant expressed on erythrocytes, the colonic mucosa and other tissues. This epitope, whose structure is Siaalpha2,3[GalNAcbeta1,4]Gal beta1,4GlcNAc, is synthesized by a beta1,4 N-acetylgalactosaminyltransferase (beta4GalNAc-T) that transfers a beta1,4-linked GalNAc to the galactose residue of an alpha2,3-sialylated chain. We have cloned from human colon carcinoma Caco2 cells a cDNA whose transfection in COS cells induces a GalNAc-T active on sialylated but not on asialylated fetuin and putatively represents the human Sd(a) beta4GalNAc-T. The cDNA predicts a 566 aa protein showing 66.6% and 39% identity with mouse CT beta4GalNAc-T and human GM2/GD2 synthase, respectively, with a typical type II glycosyltransferase organization, no potential N-glycosylation sites and a 67 aa cytoplasmic tail, which is probably the longest among the glycosyltransferases cloned to date. The gene maps in chromosome 17q23, and is composed of at least 11 exons. Exons 2-11 are homologous to exons 2-11 of the previously cloned CT beta4GalNAc-T from murine cytotoxic T lymphocytes while exons 1 of the two enzymes are totally different. The mRNA is expressed at a high level in differentiated Caco2 cells and in colonic mucosa and at a much lower level in lymphocytes and other colon cancer cell lines.
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PMID:Molecular cloning of the human beta1,4 N-acetylgalactosaminyltransferase responsible for the biosynthesis of the Sd(a) histo-blood group antigen: the sequence predicts a very long cytoplasmic domain. 1468 33


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