Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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It has been proposed recently that gastroesophageal reflux disease (GERD) patients may be categorized into three distinct groups exhibiting non-erosive reflux disease (NERD), erosive reflux disease (ERD), and Barrett's esophagus (BE). Measurement of relative gene expression levels was undertaken to identify distinct molecular subclasses in different variants of gastroesophageal disease. The measurements were made with Affymetrix U133A 2.0 GeneChips and RNA isolated from mucosal samples of normal squamous esophageal epithelium from 24, 28, and 26 patients with NERD, ERD and BE, respectively. Statistical testing of microarray data showed that gene expression profiles are discriminative for BE and NERD, but not for combinations of BE and ERD or NERD and ERD. In addition, women developing NERD exhibited transcriptional patterns that differed from those of men with BE. In clustering analyses, we did not observe correlations between sex and assignment of gene expression profile of ERD patients to either the NERD or the BE group. Although the biological significance of the identified genes remains uncertain, we hypothesize that GERD is a monophyletic disease that develops with the onset of gastroesophageal reflux and represents two main molecular classes, which may result in different progressions to inflammatory process within esophageal epithelium modulated by sexual dimorphism. While normal epithelium samples from NERD and BE patients are molecularly homogeneous, esophageal mucosa from ERD patients is molecularly similar to either NERD or BE. These findings may be useful for defining molecular markers which could predict potential progression to Barrett's metaplasia among patients with reflux disease.
J Mol Med (Berl) 2006 Oct
PMID:Three clinical variants of gastroesophageal reflux disease form two distinct gene expression signatures. 1692 68

Her-2/neu is a protooncogene frequently overexpressed in breast cancer, recently found to be also overexpressed in carcinoma arising on Barrett esophagus (BE). Immunohistochemistry and fluorescence in situ hybridization (FISH) are conventionally used for Her-2 testing in carcinomas, but a single assay is not yet accepted as a "gold standard" in BE. To evaluate the correlation between histopathology variables and gene expression/amplification in the sequence BE-low grade dysplasia-high grade dysplasia-adenocarcinoma, fifty esophageal specimens from patients with a diagnosis of BE (21 BE, 4 low-grade dysplasia, 12 high-grade dysplasia, and 13 adenocarcinomas) were evaluated. Histopathologic evaluation was carried out using hematoxylin and eosin staining. Paraffin-embedded tissues were investigated for Her-2 by immunohistochemistry (HercepTest) and FISH. HercepTest was scored 0, 1+, 2+, and 3+ depending on the percentage (cut off 10%) of membrane staining, whereas gene assessment evaluated by FISH was based on the ratio between Her-2/neu and the 17 chromosome copy number. There was a positive correlation between gene amplification and protein overexpression. No case with HercepTest scoring 0 or 1+ displayed gene amplification, but this was present in 20% of cases scoring 2+ and in all cases scoring 3+. Her-2/neu amplification or overexpression was never observed in BE. Gene amplification and overexpression was observed in more than 50% of dysplasias and adenocarcinomas. Her-2/neu amplification/overexpression might be considered as a marker of progression from BE to dysplasia. FISH may represent a useful diagnostic tool to integrate the result of HercepTest for selecting patients for more targeted therapeutic approaches.
Diagn Mol Pathol 2006 Sep
PMID:Her-2/neu in barrett esophagus: a comparative study between histology, immunohistochemistry, and fluorescence in situ hybridization. 1693 66

Epigenetic alterations, represented by aberrant DNA methylation, are deeply involved in human cancers. In gastric cancers, tumor-suppressor genes are inactivated more frequently by promoter methylation than by mutations. We recently showed that H. pylori infection, a potent gastric carcinogenic factor, induces methylation of specific genes in the gastric mucosae. When the methylation levels were analyzed in the gastric mucosae of healthy volunteers, cases with a single gastric cancer, and cases with multiple gastric cancers, who have increasing levels of risks for gastric cancers, there was a significant increasing trend in the methylation levels among the individuals without current H. pylori infection. This finding unequivocally showed the presence of an epigenetic field for cancerization. The degree of the field defect was measured more conveniently using methylation levels of marker genes than using those of tumor-suppressor genes. The presence of an epigenetic field for cancerization has been indicated for liver, colon, Barrett's esophageal, lung, breast, and renal cancers. Since decreased transcription is involved in the specificity of methylated genes, it is likely that specific genes are methylated according to carcinogenic factors. These findings emphasize the usefulness of DNA methylation as a marker for past exposure to carcinogens and future risk of cancer development.
J Biochem Mol Biol 2007 Mar 31
PMID:Epigenetic field for cancerization. 1739 62

Barrett's esophagus is characterized by the replacement of squamous epithelium with specialized intestinal metaplastic mucosa. The exact mechanisms of initiation and development of Barrett's metaplasia remain unknown, but a hypothesis of "successful adaptation" against noxious reflux components has been proposed. To search for the repertoire of adaptation mechanisms of Barrett's metaplasia, we employed high-throughput functional genomic and proteomic methods that defined the molecular background of metaplastic mucosa resistance to reflux. Transcriptional profiling was established for 23 pairs of esophageal squamous epithelium and Barrett's metaplasia tissue samples using Affymetrix U133A 2.0 GeneChips and validated by quantitative real-time polymerase chain reaction. Differences in protein composition were assessed by electrophoretic and mass-spectrometry-based methods. Among 2,822 genes differentially expressed between Barrett's metaplasia and squamous epithelium, we observed significantly overexpressed metaplastic mucosa genes that encode cytokines and growth factors, constituents of extracellular matrix, basement membrane and tight junctions, and proteins involved in prostaglandin and phosphoinositol metabolism, nitric oxide production, and bioenergetics. Their expression likely reflects defense and repair responses of metaplastic mucosa, whereas overexpression of genes encoding heat shock proteins and several protein kinases in squamous epithelium may reflect lower resistance of normal esophageal epithelium than Barrett's metaplasia to reflux components. Despite the methodological and interpretative difficulties in data analyses discussed in this paper, our studies confirm that Barrett's metaplasia may be regarded as a specific microevolution allowing for accumulation of mucosal morphological and physiological changes that better protect against reflux injury.
J Mol Med (Berl) 2007 Jul
PMID:Molecular defense mechanisms of Barrett's metaplasia estimated by an integrative genomics. 1741 42

Although serine proteases are found in all kinds of cellular organisms and many viruses, the classic "chymotrypsin family" (Group S1A by the 1998 Barrett nomenclature) has an unusual phylogenetic distribution, being especially common in animals, entirely absent from plants and protists, and rare among fungi. The distribution in Bacteria is largely restricted to the genus Streptomyces, although a few isolated occurrences in other bacteria have been reported. The family may be entirely absent from Archaea. Although more than a thousand sequences have been reported for enzymes of this type from animals, none of them have been from early diverging phyla like Porifera or Cnidaria. We now report the existence of Group S1A serine proteases in a sponge (phylum Porifera) and a jellyfish (phylum Cnidaria), making it safe to conclude that all animal groups possess these enzymes.
J Mol Evol 2006 Dec
PMID:The occurrence of type S1A serine proteases in sponge and jellyfish. 1747 31

Nitric oxide (NO) has been implicated as a potential causative factor for endogenous p53 mutations in gastrointestinal malignancy. To investigate the role of NO in esophageal adenocarcinoma (EADC), we studied patterns of p53 mutations, expression of inducible nitric oxide synthase (iNOS) and the tissue accumulation of nitrotyrosine (NTS), a stable reaction product of NO and a marker for cellular protein damage, in human premalignant and malignant esophageal epithelia. Tissues were obtained from patients with gastroesophageal reflux disease (GERD)-induced esophagitis (n = 76), Barrett's esophagus (BE; n = 119) and primary EADC (n = 54). DNA sequencing was used to characterize p53 mutations, RT-PCR to study iNOS mRNA expression, and immunohistochemistry to study NTS. Relative to self-matched normal epithelia, a progressive increase in iNOS mRNA expression was seen in GERD (30%; 23/76), BE (48%; 57/119), and EADC (63%; 34/54) tissues (P < 0.001). Among patients with EADC, elevated levels of NTS immunoreactivity were more frequent in tumors with p53 mutations (11/21; 52%) compared with tumors with wild-type p53 (9/33; 27%; P = 0.063), and specifically in tumors with p53 mutations at CpG dinucleotides (10/12; 83%) compared with non-CpG p53 mutations (1/9; 11%; P = 0.008). The increasing frequency of iNOS (mRNA) overexpression in GERD, BE and EADC supports the hypothesis that an active inflammatory process, most likely a consequence of GERD, underlies molecular progression to EADC. The highly significant association between NTS, reflecting chronic NO-induced cellular protein damage, and endogenous p53 mutations at CpG dinucleotides, provides further evidence for a molecular link between chronic inflammation and esophageal malignancy.
Mol Carcinog 2008 Apr
PMID:Inducible nitric oxide synthase, nitrotyrosine and p53 mutations in the molecular pathogenesis of Barrett's esophagus and esophageal adenocarcinoma. 1784 24

Barrett's esophagus represents a well-defined precursor lesion of esophageal adenocarcinoma, although only a subset of patients with these lesions advances to invasive cancer. Currently, reliable markers predicting neoplastic progression in Barrett's esophagus are lacking. The only clinically useful risk factor is the presence of dysplasia in Barrett's epithelium, but its use as a prognostic marker of disease progression has several significant limitations. Thus, identification of biomarkers of potential prognostic value in dysplasia development in Barrett's esophagus is highly important. The aim of the study was to determine if expression levels of selected genes support histologic diagnosis of dysplastic changes in Barrett's esophagus. Upon rigorous sampling and independent histopathologic examination of endoscopic specimens by two experienced gastrointestinal pathologists, 56 patients with Barrett's esophagus (16 negative for dysplasia, 15 with indefinite, 21 with low-grade, and 4 with high-grade dysplasia) were selected for molecular analysis. The relative mRNA levels of ten selected genes were estimated by quantitative real-time polymerase chain reaction (PCR) analysis. Although expression of nine genes showed trends toward down- or upregulation during progression from Barrett's esophagus without dysplasia to Barrett's esophagus with high-grade dysplasia, only a decrease in S100A2 mRNA levels was statistically significant (P<0.05). However, there was considerable variation among individuals and significant overlapping of ranges. Furthermore, detailed, comparative analysis of serial samples from Barrett's mucosa and normal squamous epithelium shows large intra-individual variability of gene expression levels. In conclusion, expression of this set of ten genes cannot be used as a molecular marker aiding histological examination of dysplasia in Barrett's esophagus. Significant inter- and intra-patient variations of gene expression levels makes use of the selected genes impractical.
J Mol Med (Berl) 2008 Feb
PMID:Large intra- and inter-individual variability of genes expression levels limits potential predictive value of molecular diagnosis of dysplasia in Barrett's esophagus. 1795 95

Polypeptide ligands have long been recognized as primary signaling molecules in diverse physiological processes in animal systems. Recent studies in plants have provided major breakthroughs with the discovery that small polypeptides are also involved in many plant biological processes, indicating that the use of polypeptides as signaling molecules in cell-to-cell communication is evolutionarily conserved. The CLAVATA3 (CLV3)/ENDOSPERM SURROUNDING REGION (ESR)-related (CLE) proteins are currently the best understood family of small polypeptides in plants. The recent isolation of MCLV3 from Arabidopsis and TDIF from a Zinnia cell culture system indicates that biologically active CLE polypeptides are produced by post-translational proteolysis and modification, similar to peptide hormone production in animals and yeast. Here, we review exciting discoveries involving the identification of the CLE proteins and their functions in various aspects of plant development, including restriction of stem cell accumulation by CLV3 and inhibition of xylem differentiation by TDIF.
Cell Mol Life Sci 2008 Mar
PMID:The CLE family of plant polypeptide signaling molecules. 1803 20

The frequency of oesophageal adenocarcinoma is increasing in Western countries for unknown reasons, and correlates with a corresponding increase in the pre-malignant condition, Barrett's Oesophagus, which raises the risk of adenocarcinoma by some 40- to 125-fold. We have examined how disease progression correlates with changes in expression of the p14ARF (ARF) tumour suppressor, a key regulator of the p53 tumour suppressor pathway that is silenced in some 30% of cancers overall, but for which a role in oesophageal cancer is unclear. We have used quantitative PCR, RT-PCR, methylation-specific PCR and chromatin-immunoprecipitation to examine the regulation and function of ARF in oesophageal adenocarcinoma tissue specimens and cell lines. We find highly significant reductions (P< 0.001) in ARF expression during disease progression from normal oesophageal epithelium to Barrett's Oesophagus to adenocarcinoma, with 57/76 (75%) adenocarcinomas displaying undetectable levels of ARF expression. Retention of ARF expression in adenocarcinoma is a highly significant indicator of increased survival (P< 0.001) and outperforms all clinical variables in a multivariate model. CpG methylation as well as histone H3 methylation of lysines 9 and 27 contribute independently to ARF gene silencing in adenocarcinoma cell lines and can be reversed by 5-aza-2'-deoxycytidine. The results suggest that silencing of ARF is involved in the pathogenesis of oesophageal adenocarcinoma and show that either DNA or histone methylation can provide the primary mechanism for ARF gene silencing. Silencing of ARF could provide a useful marker for increased risk of progression and poor prognosis.
J Cell Mol Med 2009 Feb
PMID:Progressive silencing of p14ARF in oesophageal adenocarcinoma. 1841 May 30

Cytochrome P450 1B1 (CYP1B1) mRNA is constitutively expressed in most normal extra-hepatic tissues; however the protein is not detectable in these tissues but is expressed in a wide variety of tumors. CYP1B1 is responsible for the activation of a number of carcinogens present in tobacco smoke and food. A surgical model of rat esophageal tumorigenesis, promoted by gastric or duodenal reflux was used to determine CYP1B1 expression in premalignant esophageal tissue. Immunohistochemistry was performed using a modified amplified fluorescein tyramide protocol. CYP1B1 was not observed in normal esophageal mucosa, submucosa, or muscularis mucosa. Animals exposed to gastric reflux developed mild hyperplasia. Varying degrees of hyperplasia were observed in the duodenal reflux group. All regions of hyperplasia showed moderate or strong CYP1B1 immunoreactivity. Duodenal reflux induced a small number of premalignant changes: immunoreactivity was absent from the epithelium of squamous dysplasia (0/10), Barrett's esophagus (0/7), and majority of dysplastic Barrett's esophagus (1/4). Moderate or strong immunoreactivity was observed in the majority (7/8) of squamous cell carcinomas (SCCs) in situ. Immunoreactivity was also observed in the lamina propria and submucosa in association with inflammation, regardless of the severity of inflammation. The expression of CYP1B1 in hyperplasia, SCCs in situ, or in association with inflammation may increase the production of carcinogenic metabolites, which may promote esophageal tumorigenesis.
Mol Carcinog 2009 Feb
PMID:Cytochrome P450 1B1 expression in rat esophageal tumorigenesis promoted by gastric and duodenal reflux. 1861 92


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