Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myxoma is the most common benign neoplasm of the heart. This work is the first to present an unusual left atrium and mitral valve cardiac myxoma which cannot be completely resected. This cardiac myxoma was also associated with abundant mucopolysaccharidic matrix, including mucin. Mucin gene expression is cell- and tissue-specific, with variations during cell differentiation and inflammation, and is altered during carcinogenesis. The expression of mucin genes in cardiac myxoma has never been elucidated previously. Detailed immunohistochemical analysis of MUC1, MUC2 and MUC5AC has been performed in this left atrium and mitral valve myxoma. Notably, the expressions of mucins in cardiac myxoma must be further evaluated.
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PMID:Mucin gene expression in cardiac myxoma. 1511 1

Although general characteristics of intraductal papillary mucinous neoplasms (IPMNs) and their delineation from other pancreatic tumors have been well established, several issues regarding their biology and management remain unresolved. It has been noted briefly by us and other authors that there are different types of papillae in IPMNs; however, their frequency, biologic significance, and clinical relevance are unknown. In this study, the association of different papillary patterns with clinical, pathologic, and biologic parameters was studied in 74 IPMNs, and the expression profile of CDX2 (a specific marker and one of the key determinants of intestinal "programming," and a tumor suppressor) was determined immunohistochemically in addition to MUC1 (a marker of an "aggressive" phenotype in pancreatic neoplasia) and MUC2 ("intestinal type mucin," a marker of the "indolent" phenotype, and a tumor suppressor). The patterns of papillae identified and their association with these parameters were as follows: 1) The intestinal-type (Yonezawa's dark-cell type), similar to villous adenomas, was seen in 26 of 74 (35%) cases. The majority harbored carcinoma in situ (85%) or borderline atypia (15%). They tended to be large (mean, 5.5 cm). Most expressed CDX2 (95%) and MUC2 (92%) but not MUC1 (8%). This type was more commonly associated with colloid-type invasion (14 of 16 invasive carcinomas were of colloid type). 2) The pancreatobiliary type, characterized by arborizing papillae lined by cuboidal cells resembling papillary neoplasms of the biliary tract, was present in 22% of the cases. These were mostly graded as carcinoma in situ (94%); they rarely expressed CDX2 (6%) or MUC2 (19%) but often showed MUC1 labeling (44%). This pattern was more commonly associated with the tubular type of invasive carcinoma and had a slight tendency for a more aggressive clinical course. 3) The null type was characterized by abundant apical mucin and basally located nuclei, similar to the gastric foveolar epithelium. Thirty-one percent of IPMNs had this type of papillae, but this pattern was also present in the background of other IPMNs and in the cystic components of most cases as well. Most pure null-type IPMNs were devoid of complexity and consequently classified as adenoma (48%). They tended to be small (mean, 2.6 cm), were often negative for CDX2, MUC1, and MUC2, and were rarely associated with invasive carcinoma. 4) Some IPMNs (12%) exhibited features that were difficult to classify, and 2 cases had a mixture of pancreatobiliary and intestinal types of papillae. In conclusion, IPMNs include pathologically and biologically distinct epithelial patterns. CDX2 and MUC2 expression is relatively specific for the intestinal type papillae, confirming that these IPMNs indeed exhibit intestinal differentiation. Their close association with colloid carcinoma, which also shows consistent MUC2 and CDX2 expression, supports the existence of an intestinal pathway of carcinogenesis. This "metaplastic" pathway may reflect different genetic events in the development of these IPMNs, and the presence of intestinal differentiation may potentially be used in prognostication and stratification of patients into appropriate treatment categories.
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PMID:Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas. 1522 52

In order to evaluate the significance of altered expression of mucin and cytokeratin during gallbladder carcinogenesis, we characterized the expressional profiles of MUC1, MUC2, MUC5AC, MUC6, CK7 and CK20 in 33 normal mucosa, 31 adenomas, 55 dysplasias and 131 carcinomas of the gallbladder. In normal gallbladder mucosa, the expressions of MUC5AC and MUC6 were diffuse and MUC1 expression was absent. However, in adenomas, dysplasias and carcinomas, the expressions of MUC5AC and MUC6 tended to decrease, whereas MUC1 expression was elevated. MUC2 and CK20 were infrequently expressed in all of the gallbladder epithelia, but adenomas expressing MUC2 and/or CK20 were more frequently associated with carcinomas and showed a higher grade of atypia than those without these antigens. In carcinomas, MUC1 expression was related to invasive growth, lymph node metastasis and a non-papillotubular type, whereas MUC6 expression was related to non-invasive growth. CK7 was diffusely expressed in almost all lesions, but carcinomas with a loss of CK7 expression showed poor survival. In conclusion, normal gallbladder mucosa has a gastric phenotype, but during carcinogenesis and tumor progression, the gastric phenotype is gradually lost and the aberrant expression of MUC1 occurs. The intestinal phenotype is not common in the gallbladder.
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PMID:Phenotypic alterations of mucins and cytokeratins during gallbladder carcinogenesis. 1526 Aug 48

The MUC1 mucin, found on the luminal surface of simple epithelial cells is upregulated and aberrantly glycosylated in many carcinomas particularly breast and ovarian. MUC1 expressed by normal mammary epithelial cells, carries core 2 glycans but in breast carcinomas the simple core 1 based glycans are added. The binding of the monoclonal antibody SM3 to its peptide epitope in the tandem repeat of MUC1 is blocked by the branched core 2 glycans found on MUC1 expressed by normal cells. Thus SM3 does not bind to MUC1 expressed by normal mammary epithelial cells but reacts with more than 90% of breast carcinomas, suggesting that the loss of at least some core 2 glycans is a very common event in breast carcinogenesis. To determine if the change in glycosylation observed in breast carcinomas confers an advantage to cancer cells, murine mammary carcinoma cell lines were developed that express MUC1 carrying core 2 or core 1 linked glycans. The in vivo growth rate in wild-type and nude mice were identical regardless of the O-glycosylation patterns. However, the tumors that grew out of wild-type mice lost most of their MUC1 expression. In contrast, in MUC1 transgenic mice, where expression of MUC1 was retained by the tumor, a striking difference in growth rate was observed. In these mice, cells expressing core 1 glycans grew significantly faster than cells expressing core 2 glycans. These data suggest that MUC1 transgenic mice are more tolerant to core 1 expressing tumors than to tumors expressing core 2.
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PMID:Sialylated core 1 based O-linked glycans enhance the growth rate of mammary carcinoma cells in MUC1 transgenic mice. 1537 43

Apoptosis is a physiological mechanism responsible for a wide range of cellular processes during growth, development, carcinogenesis, and inflammation. In this study, we determined whether MUC1 affects Fas ligand (FasL)-induced apoptosis using MUC1 expressing (MUC1(+)) and MUC1(-) cells. Following treatment with 50 nM FasL, apoptosis, caspase-8 activity, and cell surface Fas receptor were measured by cytosolic nucleosome ELISA, colorimetric enzyme assay, and immunofluorescence analysis, respectively. Our results showed that (i) treatment with FasL increased caspase-8 activity (maximum at 4 h) and apoptosis (maximum at 8 h) in both MUC1(+) and MUC1(-) cells, (ii) FasL-induced caspase-8 activity and apoptosis were significantly greater in MUC1(+) cells compared with MUC1(-) cells, (iii) FasL treatment increased cell surface expression of Fas receptor in MUC1(+) cells to a greater extent compared with MUC1(-) cells, (iv) increased cell surface expression of Fas in MUC1(+) cells was not blocked by an inhibitor of protein synthesis (cycloheximide), but was completely abrogated by brefeldin A, an inhibitor of post-translational protein trafficking to the cell surface, and (v) brefeldin A inhibited the increased sensitivity of MUC1(+) cells to FasL-induced apoptosis. We conclude that MUC1(+) cells were more sensitive to FasL-induced apoptosis compared with MUC1(-) cells due to up-regulation of Fas receptor on the cell surface by a mechanism involving increased intracellular trafficking.
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PMID:Augmentation of Fas ligand-induced apoptosis by MUC1 mucin. 1580 6

MUC1 mucin is a high molecular weight, type I transmembrane glycoprotein. High and aberrant expression of MUC1 is observed in various types of tumors, which make it an ideal target for tumor biotherapy as well as a biomarker for tumor diagnosis and prognosis. MUC1/Y is an isoform of MUC1 generated by alternative splicing. Specific expression of MUC1/Y in breast cancer as well as its involvement in tumor cell signal transduction have been reported. In order to purify peptides containing MUC1/Y-specific epitope in E. coli and prepare MUC1/Y-specific antibody, DNA fragment encoding the MUC1/Y-specific peptide was amplified by PCR using MUC1/Y full length cDNA as the template and cloned into fusion expression vector pGEX-2T, resulting pGEX-Y30. DNA sequencing was performed to confirm the correct amplification and orientation of the target sequence. Competent E. coli DH5alpha was transformed with pGEX-Y30 and the expression was induced for 4-5 hours in 0.2 mmol/L IPTG at 30 degrees C and 37 degrees C. Expressed proteins were released from the cells by ultrasonication or B-PER II reagent treatments. The fusion protein GST-Y30 were purified by affinity and anion exchange columns and identified by SDS-PAGE and Western-blotting. Polyclonal antibody was prepared by immunizing rabbits with the GST-Y30 protein for 4 times with intervals of 3 weeks and purified by GST column. Western blotting, ELISA and immunohistochemistry analysis were carried out using the purified antibody to confirm its MUC1/Y-binding capacity and specificity. The expressed fusion protein GST-Y30 is about 31 kD in size and represented about 20% of total cellular proteins. The majority of the GST-Y30 protein existed as soluble form when the induction was carried out at both 30 degrees C and 37 degrees C. After the two-step purification, the purity of GST-Y30 was about 94%. The titer of polyserum generated by GST-Y30 immunization was 1:320,000 by ELISA. The antiserum showed MUC1/Y specificity and can recognize MUC1/Y on MCF7 cell. The MUC1/Y-specific polyclonal antibody can be used for studying the role of MUC1/Y in carcinogenesis.
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PMID:[Soluble expression of peptide containing MUC1/Y-specific epitope in Escherichia coli and preparation of the antibody]. 1596 18

Pancreatic juice is a promising type of diagnostic sample for pancreatic cancer, and members of the mucin (MUC) family are diagnostic candidates. To evaluate the utility of MUC family members as diagnostic markers, we measured MUC mRNA expression in pancreatic tissues and pancreatic juice obtained from patients with different pancreatic diseases as well as in pancreatic cancer cell lines by real-time PCR. Furthermore, to support the possibility of early diagnosis by quantification of MUC1 and MUC5AC, immunohistochemistry and microdissection-based quantitative analysis of mRNA were carried out. There was no significant correlation between MUC1 and MUC5AC expression in cell lines. When beta-actin was used as a reference gene, median MUC1 and MUC5AC mRNA expression levels were remarkably greater in tumoral tissues than in non-tumoral tissues, but median MUC4 and MUC6 mRNA expression levels were not. Receiver operating characteristic curve analysis showed that quantitative analysis of MUC1 and MUC5AC mRNA in pancreatic juice is better diagnostic modality than that of MUC4 and MUC6 mRNA. Immunohistochemistry showed that MUC1 and MUC5AC were highly expressed in invasive ductal carcinomas (IDC) and moderately expressed in high-grade pancreatic intraepithelial neoplasia (PanIN); no staining was observed in normal ducts. Analysis of cells isolated by microdissection showed stepwise upregulation of MUC1 and MUC5AC in the development of high-grade PanIN to IDC. Our results suggest that MUC1 and MUC5AC are upregulated stepwise in pancreatic carcinogenesis and that quantitative assessment of MUC1 and MUC5AC mRNA in pancreatic juice has high potential for preoperative diagnosis of pancreatic cancer.
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PMID:Quantitative analysis of MUC1 and MUC5AC mRNA in pancreatic juice for preoperative diagnosis of pancreatic cancer. 1605 19

Mucin core proteins are known to be present in various organs and are specifically expressed with carcinogenesis and closely associated with the prognoses of various malignant tumors in the digestive tract such as colorectal cancer. The present study evaluated correlations between mucin and p53 expression and prognosis of gallbladder cancer using surgically resected tissue specimens from 26 patients with gallbladder carcinoma surgically treated at our hospital. Immunohistochemical staining was performed using MUC 1, MUC2, and p53 monoclonal antibody. The level of antigen expression in the lesion was classified into four stages: none(-), slight(+), moderate (++), and severe (+ + +). According to the UICC classification, histopathological grading, levels of T, N, and M factors, and tumor stages were compared with regard to the correlations with mucin and p53 expression. All cases were classified into two groups according to the results of mucin immunohistochemistry: group A (MUC1, > or = ++; and MUC2, < or = +) and group B (MUC1, < ++; or MUC2, > +). Postoperative survival periods were compared between the two groups and p53-positive and -negative groups. Neither histological grading nor T factor correlated with mucin or p53 expression, respectively. Moreover, neither N factor nor M factor correlated with mucin or p53 expression. Furthermore, stage grouping did not correlate with mucin or p53 expression. However, when the correlation between the postoperative survival period and mucin expression was evaluated, the mean postoperative surgical period was significantly shorter in Group A than in Group B (1.02 years in Group A vs 2.92 years in Group B; P = 0.016). There was no relationship between postoperative survival period and p53 positivity. Mucin expression was independent of various tumor growth factors and clearly reflected the prognosis of gallbladder cancer. Because the relative malignancy of gallbladder cancer could be evaluated by examining the level of glycoprotein expression in tumor tissue, mucin could be a more important marker than p53 for predicting prognosis in gallbladder carcinoma using surgically resected tissue specimens.
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PMID:Prediction of prognosis in gallbladder carcinoma by mucin and p53 immunohistochemistry. 1611 33

A cohort of patients with intraductal growth-type intrahepatic cholangiocarcinoma (IG-ICC) and its precursor lesions, collectively termed intraductal papillary neoplasm of the liver (IPNL), was characterized with respect to demographics, clinical manifestations, perioperative management, long-term survival, and molecular features associated with carcinogenesis. A total of 122 patients with IPNL types 1 through 4, 108 patients with non-IG-ICC and 210 patients with hepatolithiasis alone were studied. Expression of CDX2, TFF1, MUC1, MUC2, MUC5AC, EGFR, and p53 was determined by using immunohistochemistry. Females predominated in those with hepatolithiasis alone and IPNL. The mean age of patients with hepatolithiasis alone was 6 to 8 years younger than that of those with IPNL. The association with hepatolithiasis in patients with IPNL types 1 and 2, IPNL types 3 and 4, and non-IG-ICC was 100%, 79%, and 64%, respectively. Mucobilia, anemia, and elevated serum carcinoembryonic antigen levels were helpful in distinguishing IG-ICC and its precursor lesions. The mean survival of patients with IPNL type 3, IPNL type 4, and non-IG-ICC was 55.5 months, 36.9 months, and 15.8 months, respectively. The incidence of expression of CDX2 and TFF1 was maximal in IPNL type 3. Expression and cellular distribution of MUC2 and CDX2 were similar. MUC5AC was strongly expressed in all patients with IPNL; EGFR and p53 were rarely expressed in patients with IPNL. In conclusion, hepatolithiasis appears to be a precipitating factor in the development of IPNL. Signs of mucobilia were specific for the diagnosis of IPNL. Expression of CDX2 and MUC2 are helpful in differentiating IPNL and non-IG-ICC. Significant differences in survival associated with the various lesions studied warrants a more aggressive surgical strategy in their management.
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PMID:Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions. 1611 40

Most pancreatic neoplasia are of ductal lineage, characterized by tubule (gland), cyst, papilla, or mucin formation and expression of mucin-related glycoproteins and oncoproteins (eg, MUC1, CA19-9, CEA, DUPAN), as well as some subsets of cytokeratin (eg, CK19). Mutations of k-ras oncogene and DPC4 are also common in ductal neoplasia and generally not seen in nonductal tumors. A variety of pancreatic neoplasia fall under the heading of ductal neoplasia. Invasive ductal adenocarcinoma (DA) is the most important and constitutes the vast majority (>85%) of pancreatic tumors. DA is characterized by insidious infiltration and rapid dissemination, despite its relatively well-differentiated histologic appearance. In some variants of DA such as undifferentiated or sarcomatoid, evidence of ductal differentiation may be lacking or only focal. The presumed precursors of DA are microscopic intraductal proliferative changes that are now termed pancreatic intraepithelial neoplasia (PanIN). PanINs comprise a neoplastic transformation ranging from early mucinous change (PanIN-1A) to frank CIS (PanIN-3). A similar (in situ) neoplastic spectrum also characterizes intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, which are cystic ductal-mucinous tumors with varying degrees of papilla formation, and may be associated with invasive carcinoma. As such, these can be regarded as mass-forming preinvasive neoplasia. Some intraductal papillary mucinous neoplasms are associated with invasive carcinoma of the colloid type. Colloid carcinoma of the pancreas appears to be a clinicopathologically distinct tumor with indolent behavior. Whereas most ductal pancreatic neoplasia are characterized by some degree of mucin formation, serous tumors, of which serous (microcystic) adenoma is the sole example, lack mucin formation, presumably because they recapitulate centroacinar ducts. They are typically benign tumors. It is recognized now that pancreatic carcinoma, like other malignant processes, is a genetic disease produced by progressive mutations in cancer-related genes. These alterations can be categorized as "early" such as k-ras mutation, HER-2/neu, PSCA, MUC5, and fascin overexpression; "intermediate" such as p16 inactivation, MUC1, and cyclin D1 overexpression; and finally as "late" such as p53 and DPC4 inactivation, BRCA2 mutation, and overexpression of ki-67, 14-3-3sigma, and mesothelin. Ductal neoplasia is the most important category among pancreatic tumors. It is important to appreciate the different types of ductal tumors because they vary greatly in their clinicopathologic characteristics and prognosis. Understanding the molecular mechanisms of ductal carcinogenesis will help develop more efficient prevention and therapy of these tumors.
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PMID:Ductal neoplasia of the pancreas: nosologic, clinicopathologic, and biologic aspects. 1618 79


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