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Nicole Porchet - One of the best experts on this subject based on the ideXlab platform.
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normal respiratory mucosa precursor lesions and lung carcinomas differential expression of human mucin genes
Frontiers in Bioscience, 2001Co-Authors: Mariechristine Copin, Fabienne Escande, J P Aubert, Marie-pierre Buisine, L Devisme, Xavier Leroy, B Gosselin, Nicole PorchetAbstract:Mucins are glycoproteins synthesized by epithelial cells and thought to promote tumor-cell invasion. Eight human mucin genes have been well characterized: MUC2, MUC5AC, MUC5B, MUC6 map to 11p15.5 and encode secretory gel forming mucins while MUC1, MUC3, MUC4, MUC7 are scattered on different chromosomes and encode membrane-bound or secreted mucins. The expression pattern of the mucin genes is complex in normal airways involving six genes, mainly MUC5AC and MUC5B in mucus-producing cells and MUC4 in a wide array of epithelial cells. MUC5AC overexpression in metaplasia, dysplasia and normal epithelium adjacent to squamous cell carcinoma provides additional arguments for a mucous cell origin of preneoplastic squamous lesions. MUC5AC and MUC5B expression is related to mucus formation in adenocarcinomas. Mucinous bronchioloalveolar carcinoma (BAC) has a particular pattern of mucin gene expression indicating that it has sustained a well-differentiated phenotype similar to the goblet cell, correlated with distinctive features i.e. a noninvasive pattern and a better prognosis than nonBACs. MUC4 is the earlier mucin gene expressed in the foregut, before epithelial differentiation and is expressed independently of mucus secretion both in normal adult airways and carcinomas. These findings are in favor the histogenetic theory of non-small-cell carcinoma originating from a pluripotent mucous cell.
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developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands i stomach a relationship to gastric carcinoma
Journal of Histochemistry and Cytochemistry, 2000Co-Authors: Marie-pierre Buisine, Nicole Porchet, Jean-pierre Aubert, Mariechristine Copin, L Devisme, V Maunoury, Elisabeth Deschodt, Bernard GosselinAbstract:Studies were undertaken to provide information regarding cell-specific expression of mucin genes in stomach and their relation to developmental and neoplastic patterns of epithelial cytodifferentiation. In situ hybridization was used to study mRNA expression of eight mucin genes (MUC1-4, MUC5AC, MUC5B, MUC6, MUC7) in stomach of 13 human embryos and fetuses (8-27 weeks' gestation), comparing these with normal, metaplastic, and neoplastic adult tissues. These investigations have demonstrated that MUC1, MUC4, MUC5AC, MUC5B, and MUC6 are already expressed in the embryonic stomach at 8 weeks of gestation. MUC3 mRNA expression can be observed from 10.5 weeks of gestation. MUC2 is expressed at later stages, concomitant with mucous gland cytodifferentiation. Normal adult stomach is characterized by strong expression of MUC1, MUC5AC, and MUC6, less prominent MUC2, and sporadic MUC3 and MUC4, without MUC5B and MUC7. Intestinal metaplasia is characterized by an intestinal-type pattern with MUC2 and MUC3 mRNA expression. Gastric carcinomas exhibit altered mucin gene expression patterns with disappearance of MUC5AC and MUC6 mRNAs in some tumor glands, abnormal expression of MUC2, and reappearance of MUC5B mRNAs. In conclusion, we have observed that patterns of mucin gene expression in embryonic and fetal stomach could show similarities with some gastric carcinomas in adults. Differences in mucin gene expression in developmental, metaplastic, and neoplastic stomach compared to normal adult stomach suggest a possible regulatory role for their products in gastric epithelial cell proliferation and differentiation.
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transdermal nicotine decreases mucosal il 8 expression but has no effect on mucin gene expression in ulcerative colitis
Inflammatory Bowel Diseases, 1998Co-Authors: Beatrice Louvet, Nicole Porchet, Marie-pierre Buisine, Jean-pierre Aubert, Pierre Desreumaux, William J Tremaine, Monique Capron, Antoine Cortot, Jeanfrederic Colombel, William J SandbornAbstract:Abstract Our goal was to determine the effect of transdermal nicotine on cytokine and mucin gene transcription in ulcerative colitis (UC). Sixty-four nonsmoking patients with active UC were randomly assigned to transdermal nicotine (maximum dose 22 mg/day) or placebo for 4 weeks. Clinical assessment and colonic mucosal biopsies were obtained at entry and after 4 weeks. Inflammatory and immunoregulatory cytokines were assessed by qualitative reverse transcriptase-polymerase chain reaction (RT-PCR). Based on this initial screen. IL-8 mRNA levels were measured by RT-competitive PCR. MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC6 mRNA concentrations were measured by quantitative dot blot analysis. Cytokine mRNA expression, except for IL-8, was similar in all patients. IL-8 mRNA levels were significantly decreased in the colonic mucosa of nicotine-treated patients who improved (p = 0.04). IL-8 mRNA values were similar before and after treatment in nonresponding nicotine-treated patients and in all placebo-treated patients. Mucin gene expression was similar in all patient groups. Beneficial effects of transdermal nicotine in active UC may result from decrease of IL-8 expression at the transcriptional level. Transdermal nicotine has no effect on mucin gene transcription.
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human mucin genes muc2 muc3 muc4 muc5ac muc5b and MUC6 express stable and extremely large mrnas and exhibit a variable length polymorphism an improved method to analyze large mrnas
Journal of Biological Chemistry, 1998Co-Authors: Virginie Debailleul, Jean-pierre Aubert, Anne Laine, Guillemette Huet, Pascal Mathon, Maud Collyn Dhooghe, Nicole PorchetAbstract:Abstract Of the nine mucin genes that have been characterized, only MUC1 and MUC7 have been fully sequenced, and their transcripts can be detected as distinct bands of predicted size by Northern blot analysis. In contrast, the RNA patterns observed for each of the other MUC genes have usually shown a very high degree of polydispersity. This polydispersity has been believed to be one of the typical features of the mucin mRNAs, but until now, its origin has remained unexplained. In the work described in the present paper, we investigated two possible kinds of explanation for this phenomenon: namely that the extensive polydispersity results from a biological mechanism or that it is artifactual in origin. The data obtained, as a result of improving the purification and blotting methods, allowed us to show that in all of the tissues analyzed, each of the genes, MUC2–6, expresses mRNAs that are stable and are of an unusually large size to be found in eukaryotes (14–24 kilobases). Moreover, allelic variations in length of these mucin transcripts were observed. We demonstrate that these variations are directly related to the variable number of tandem repeat polymorphisms seen at the DNA level.
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altered expression of muc2 muc4 and muc5 mucin genes in pancreas tissues and cancer cell lines
Gastroenterology, 1994Co-Authors: Cristina Balague, Nicole Porchet, Jean-pierre Aubert, Young S. Kim, Gemma Gambus, Cristina Carrato, Francisco X RealAbstract:Abstract Background/Aims: Neoplastic transformation of epithelial cells is commonly associated with altered synthesis and structure of mucin glycoproteins. The aim of the study was to determine if altered mucin gene expression takes place in pancreas cancer. Methods: To examine mucin gene expression in normal pancreas and pancreas cancer, antibodies detecting the MUC1, MUC2, MUC5B, and MUC5C apomucins were used in immunohistochemical techniques and complementary DNA probes specific for the MUC1-MUC5 genes were used in Northern blots. Results: MUC1 is the major apomucin expressed in normal pancreas, whereas MUC2-MUC5 are weakly expressed or undetectable. In pancreas cancer tissues and cell lines, increased expression of MUC2, MUC4, and MUC5C is shown. The cytoplasmic expression of MUC2 and MUC5C in tumor cells suggests that these apomucins are underglycosylated and abnormally compartmentalized. Conclusions: Enhanced expression of MUC2, MUC4, and MUC5C genes is a frequent event in pancreas cancer and may contribute to the alterations in the biochemical structure of pancreas cancer mucins.
I Van Seuningen - One of the best experts on this subject based on the ideXlab platform.
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epigenetic regulation dna methylation histone modifications of the 11p15 mucin genes muc2 muc5ac muc5b MUC6 in epithelial cancer cells
Oncogene, 2007Co-Authors: Audrey Vincent, J P Aubert, Michael Perrais, Jeanluc Desseyn, Pascal Pigny, I Van SeuningenAbstract:Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes ( MUC2 , MUC5AC , MUC5B , MUC6 ) in epithelial cancer cells
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Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells
Oncogene, 2007Co-Authors: Audrey Vincent, J P Aubert, Michael Perrais, Jeanluc Desseyn, Pascal Pigny, I Van SeuningenAbstract:The human genes MUC2, MUC5AC, MUC5B and MUC6 are clustered on chromosome 11 and encode large secreted gel-forming mucins. The frequent occurrence of their silencing in cancers and the GC-rich structure of their promoters led us to study the influence of epigenetics on their expression. Pre-and post-confluent cells were treated with demethylating agent 5-aza-2 0-deoxycytidine and histone deacetylase (HDAC) inhibitor, trichostatin A. Mapping of methylated cytosines was performed by bisulfite-treated genomic DNA sequencing. Histone modification status at the promoters was assessed by chromatin immunoprecipitation assays. Our results indicate that MUC2 was regulated by site-specific DNA methylation associated with establishment of a repressive histone code, whereas hypermethylation of MUC5B promoter was the major mechanism responsible for its silencing. DNA methyltransferase 1 was identified by small interfering RNA approach as a regulator of MUC2 and MUC5B endogenous expression that was potentiated by HDAC2. MUC2 and MUC5B epigenetic regulation was cell-specific, depended on cell differentiation status and inhibited their activation by Sp1. The expression of MUC5AC was rarely influenced by epigenetic mechanisms and methylation of MUC6 promoter was not correlated to its silencing. In conclusion, this study demonstrates the important role for methylation and/or histone modifications in regulating the 11p15 mucin genes in epithelial cancer cells.
J P Aubert - One of the best experts on this subject based on the ideXlab platform.
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epigenetic regulation dna methylation histone modifications of the 11p15 mucin genes muc2 muc5ac muc5b MUC6 in epithelial cancer cells
Oncogene, 2007Co-Authors: Audrey Vincent, J P Aubert, Michael Perrais, Jeanluc Desseyn, Pascal Pigny, I Van SeuningenAbstract:Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes ( MUC2 , MUC5AC , MUC5B , MUC6 ) in epithelial cancer cells
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Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells
Oncogene, 2007Co-Authors: Audrey Vincent, J P Aubert, Michael Perrais, Jeanluc Desseyn, Pascal Pigny, I Van SeuningenAbstract:The human genes MUC2, MUC5AC, MUC5B and MUC6 are clustered on chromosome 11 and encode large secreted gel-forming mucins. The frequent occurrence of their silencing in cancers and the GC-rich structure of their promoters led us to study the influence of epigenetics on their expression. Pre-and post-confluent cells were treated with demethylating agent 5-aza-2 0-deoxycytidine and histone deacetylase (HDAC) inhibitor, trichostatin A. Mapping of methylated cytosines was performed by bisulfite-treated genomic DNA sequencing. Histone modification status at the promoters was assessed by chromatin immunoprecipitation assays. Our results indicate that MUC2 was regulated by site-specific DNA methylation associated with establishment of a repressive histone code, whereas hypermethylation of MUC5B promoter was the major mechanism responsible for its silencing. DNA methyltransferase 1 was identified by small interfering RNA approach as a regulator of MUC2 and MUC5B endogenous expression that was potentiated by HDAC2. MUC2 and MUC5B epigenetic regulation was cell-specific, depended on cell differentiation status and inhibited their activation by Sp1. The expression of MUC5AC was rarely influenced by epigenetic mechanisms and methylation of MUC6 promoter was not correlated to its silencing. In conclusion, this study demonstrates the important role for methylation and/or histone modifications in regulating the 11p15 mucin genes in epithelial cancer cells.
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normal respiratory mucosa precursor lesions and lung carcinomas differential expression of human mucin genes
Frontiers in Bioscience, 2001Co-Authors: Mariechristine Copin, Fabienne Escande, J P Aubert, Marie-pierre Buisine, L Devisme, Xavier Leroy, B Gosselin, Nicole PorchetAbstract:Mucins are glycoproteins synthesized by epithelial cells and thought to promote tumor-cell invasion. Eight human mucin genes have been well characterized: MUC2, MUC5AC, MUC5B, MUC6 map to 11p15.5 and encode secretory gel forming mucins while MUC1, MUC3, MUC4, MUC7 are scattered on different chromosomes and encode membrane-bound or secreted mucins. The expression pattern of the mucin genes is complex in normal airways involving six genes, mainly MUC5AC and MUC5B in mucus-producing cells and MUC4 in a wide array of epithelial cells. MUC5AC overexpression in metaplasia, dysplasia and normal epithelium adjacent to squamous cell carcinoma provides additional arguments for a mucous cell origin of preneoplastic squamous lesions. MUC5AC and MUC5B expression is related to mucus formation in adenocarcinomas. Mucinous bronchioloalveolar carcinoma (BAC) has a particular pattern of mucin gene expression indicating that it has sustained a well-differentiated phenotype similar to the goblet cell, correlated with distinctive features i.e. a noninvasive pattern and a better prognosis than nonBACs. MUC4 is the earlier mucin gene expressed in the foregut, before epithelial differentiation and is expressed independently of mucus secretion both in normal adult airways and carcinomas. These findings are in favor the histogenetic theory of non-small-cell carcinoma originating from a pluripotent mucous cell.
Audrey Vincent - One of the best experts on this subject based on the ideXlab platform.
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epigenetic regulation dna methylation histone modifications of the 11p15 mucin genes muc2 muc5ac muc5b MUC6 in epithelial cancer cells
Oncogene, 2007Co-Authors: Audrey Vincent, J P Aubert, Michael Perrais, Jeanluc Desseyn, Pascal Pigny, I Van SeuningenAbstract:Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes ( MUC2 , MUC5AC , MUC5B , MUC6 ) in epithelial cancer cells
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Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells
Oncogene, 2007Co-Authors: Audrey Vincent, J P Aubert, Michael Perrais, Jeanluc Desseyn, Pascal Pigny, I Van SeuningenAbstract:The human genes MUC2, MUC5AC, MUC5B and MUC6 are clustered on chromosome 11 and encode large secreted gel-forming mucins. The frequent occurrence of their silencing in cancers and the GC-rich structure of their promoters led us to study the influence of epigenetics on their expression. Pre-and post-confluent cells were treated with demethylating agent 5-aza-2 0-deoxycytidine and histone deacetylase (HDAC) inhibitor, trichostatin A. Mapping of methylated cytosines was performed by bisulfite-treated genomic DNA sequencing. Histone modification status at the promoters was assessed by chromatin immunoprecipitation assays. Our results indicate that MUC2 was regulated by site-specific DNA methylation associated with establishment of a repressive histone code, whereas hypermethylation of MUC5B promoter was the major mechanism responsible for its silencing. DNA methyltransferase 1 was identified by small interfering RNA approach as a regulator of MUC2 and MUC5B endogenous expression that was potentiated by HDAC2. MUC2 and MUC5B epigenetic regulation was cell-specific, depended on cell differentiation status and inhibited their activation by Sp1. The expression of MUC5AC was rarely influenced by epigenetic mechanisms and methylation of MUC6 promoter was not correlated to its silencing. In conclusion, this study demonstrates the important role for methylation and/or histone modifications in regulating the 11p15 mucin genes in epithelial cancer cells.
Surinder K. Batra - One of the best experts on this subject based on the ideXlab platform.
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mucins in the pathogenesis of breast cancer implications in diagnosis prognosis and therapy
Biochimica et Biophysica Acta, 2011Co-Authors: Partha Mukhopadhyay, Maneesh Jain, Surinder K. Batra, Subhankar Chakraborty, Moorthy P Ponnusamy, Imayavaramban LakshmananAbstract:Abstract Mucins are high molecular weight, multifunctional glycoproteins comprised of two structural classes—the large transmembrane mucins and the gel-forming or secreted mucins. The primary function of mucins is to protect and lubricate the luminal surfaces of epithelium-lined ducts in the human body. Recent studies have identified a differential expression of both membrane bound (MUC1, MUC4 and MUC16) and secreted mucins (MUC2, MUC5AC, MUC5B and MUC6) in breast cancer tissues when compared with the non-neoplastic breast tissues. Functional studies have also uncovered many unique roles of mucins during the progression of breast cancer, which include modulation in proliferative, invasive and metastatic potential of tumor cells. Mucins function through many unique domains that can form complex association with various signaling molecules including growth factor receptors and intercellular adhesion molecules. While there is growing information about mucins in various malignancies including breast cancer, no focused review is there on the expression and functional roles of mucins in breast cancer. In this present review, we have discussed the differential expression and functional roles of mucins in breast cancer. The potential of mucins as diagnostic and prognostic markers and as therapeutic targets in breast cancer have also been discussed.
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aberrant expression of muc4 in ovarian carcinoma diagnostic significance alone and in combination with muc1 and muc16 ca125
Modern Pathology, 2006Co-Authors: Subhash C Chauhan, Maneesh Jain, Nicolas Moniaux, Ajay P Singh, Sonny L Johansson, Lynette M Smith, Fernanda Ruiz, Surinder K. BatraAbstract:Mucins are being implicated in diagnosis, prognosis, and as therapeutic targets due to their aberrant expression in a variety of carcinomas. Here, we have analyzed the expression of MUC4 and have compared its potential usefulness in early detection and prognosis of ovarian carcinoma alone and in combination with other mucin antigens, MUC1 and MUC16. Clinical significance of the differential mucin expression was evaluated by grouping the tumor samples in early (stage I and II) and advanced (stage III and IV) stage cases and histological subtypes (serous, mucinous, endometrioid and clear cell). Correlation of these mucins with patient's survival (n=63) was determined by Kaplan-Meier analysis in order to predict their prognostic value. MUC4 showed significant overexpression in tumor cases (P<0.0001) with highest incidence (92.0%) among all three mucins. A significant overexpression of MUC1 (P<0.018) and MUC16 (P<0.0001) was also observed in 83.0 and 79.0% of tumor samples, respectively. Notably, MUC4 expression was significantly higher (Pmucins displayed overall comparable expression, nonetheless, MUC4 had highest prevalence (88.0%) compared to MUC1 (84.0%) and MUC16 (81.0%). A combined panel of MUC4 with MUC16 detected 100% of the late-stage tumor cases without compromising the specificity. Among histological subtypes, only MUC4 displayed 100% (n=5) sensitivity in mucinous ovarian tumors, while MUC1 and MUC16 detected 40 and 20% cases, respectively. The expression of MUC4, however, did not significantly correlate with the survival of the ovarian cancer patient, while a significant correlation of MUC16 with poor prognosis was observed. In conclusion, our study demonstrates that MUC4 could be a potential candidate marker for early diagnosis of epithelial ovarian carcinoma and can be utilized in combination with MUC16 to achieve greater sensitivity for the detection of late-stage tumors.
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aberrant expression of transmembrane mucins muc1 and muc4 in human prostate carcinomas
The Prostate, 2006Co-Authors: Ajay P Singh, Sangeeta Bafna, Nicolas Moniaux, Subhash C Chauhan, Sonny L Johansson, Lynette M Smith, Ming Fong Lin, Surinder K. BatraAbstract:BACKGROUND Mucins are considered important markers for early diagnosis and targeted therapy due to their aberrant and unique expression pattern during malignant progression of carcinomas. Recent findings have provided substantial evidence for the involvement of transmembrane mucins, MUC1 and MUC4, in altered cell signaling, tumor growth, and metastasis. METHODS Immunohistochemical analyses were performed on prostate tumor tissues for expression profiling of the two transmembrane mucins, MUC1 and MUC4. In cancer cell lines, the expression was studied by RT-PCR and immunoblot analyses. Cells were treated with DNA-methylase and histone-deacetylase inhibitors to examine the implication of epigenetic mechanism(s) in MUC4 regulation. RESULTS The expression of MUC4 was significantly downregulated in prostate cancer tissues (n = 38, P = 0.0026) compared to normal/benign prostatic hyperplastic regions. A faint to moderate staining was observed in 26.3% cases of cancer, while 84.2% cases of adjacent normal were positive for MUC4 with moderate to strong staining in most cases. Similar observations were made in immortalized normal prostate epithelial and cancer cell lines. MUC1 also showed a reduced expression in prostate tumor tissues; however, its expression was comparable in all normal prostate epithelial and cancer cell lines. Interestingly, we also found that epigenetic mechanism(s) might be implicated in MUC4 gene silencing. CONCLUSIONS Our data suggest that MUC4 downregulation may be of significance for diagnostic applications in prostate cancer. © 2005 Wiley-Liss, Inc.
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mucin muc gene expression in human pancreatic adenocarcinoma and chronic pancreatitis a potential role of muc4 as a tumor marker of diagnostic significance
Clinical Cancer Research, 2001Co-Authors: Mahefatiana Andrianifahanana, Nicolas Moniaux, Michael A Hollingsworth, Jean-pierre Aubert, Bruno M Schmied, Jorg Ringel, Helmut Friess, Markus W Buchler, Surinder K. BatraAbstract:Purpose: Mucins are important biomolecules that frequently display an altered expression under pathological conditions. In a search for a unique and reliable marker(s) specific for pancreatic adenocarcinoma, we investigated the expression of different MUC genes in pancreatic tumors and tumor cell lines, in chronic pancreatitis, and in the normal pancreas. Experimental Design: Total RNA from 16 pancreatic tumors, 10 chronic pancreatitis tissues, 7 normal pancreas tissues, and 15 pancreatic tumor cell lines were analyzed by reverse transcription-PCR with primers specific for MUC1 , MUC2 , MUC3 , MUC4 , MUC5AC , MUC5B , MUC6 , and MUC7 genes and by RNA slot blot analyses. Results: Our results revealed that of all of the mucins examined, only MUC4 displayed a differential expression that was specific for pancreatic adenocarcinoma. Indeed, a substantial number of tumor tissue samples (12 of 16) and tumor cell lines (11 of 15) expressed MUC4 mRNA, whereas samples from chronic pancreatitis (0 of 10) and the normal pancreas (0 of 7) tissues failed to exhibit any detectable level of this mucin. In contrast, no significant alteration was observed in the expression of the other mucins relative to that in the normal pancreas samples. Conclusions: Overall, this work demonstrates that pancreatic mucin MUC4 is a tumor-associated mucin. Furthermore, the present study introduces a novel avenue to discriminate between pancreatic adenocarcinoma and pancreatitis. Future investigations of the role played by MUC4 in pancreatic adenocarcinoma may prove to be useful in the formulation of strategies for the diagnosis and therapeutic treatment of this malignancy.