Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Syndromic and sporadic fundic gland polyps are morphologically indistinguishable but may arise via different pathogenetic mechanisms involving mutations of the adenomatous polyposis coli (APC) and its downstream target beta-catenin genes. Although a higher frequency of dysplasia has been reported in syndromic forms, the risk of developing invasive carcinoma is exceedingly low. The current study was designed to investigate whether syndromic and sporadic fundic gland polyps differ in protein expression of a number of genes that are thought to be important in the control of neoplastic transformation. A total of 262 fundic gland polyps, including 155 syndromic polyps obtained from 35 patients with familial adenomatous polyposis or Gardner's syndrome and 107 sporadic polyps randomly selected from 45 patients with gastroesophageal reflux disease or Barrett's esophagus, were included in this study. Immunohistochemical evaluation showed that loss of immunoreactivity to the antibody against the carboxyl terminus of the APC protein, presumably resulting from APC gene mutations, was more frequent in syndromic than in sporadic cases (40% versus 6.7%, P<0.001). However, immunostaining failed to show aberrant nuclear localization of beta-catenin, a protein regulated by APC, in any of the polyps, irrespective of syndromic or sporadic types. Instead, positive membranous staining for beta-catenin was observed in all the cases. In addition, the expression characteristics of 2 other proteins, c-Myc and cyclin D1, whose genes have been reported to be transcriptionally regulated by the APC/beta-catenin pathway, were similar in these two types of polyps. Furthermore, all cases, including those harboring dysplasia, showed negative nuclear staining for p53 and positive nuclear staining for retinoblastoma (RB). Taken together, these data show a lack of dysregulation in the APC/beta-catenin signaling pathway and in the expression of p53 and RB in fundic gland polyps despite a high frequency of somatic mutations of the APC and beta-catenin genes reported in these polyps. These findings may explain at least in part why fundic gland polyps show a negligible malignant potential even in the presence of dysplasia.
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PMID:Immunohistochemical evaluation of adenomatous polyposis coli, beta-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps. 1501 89

Gastroesophageal reflux disease complicated by Barrett esophagus (BE) is a major risk factor for esophageal adenocarcinoma (EA). The mechanisms whereby acid reflux may accelerate the progression from BE to EA are not known. We found that NOX1 and NOX5-S were the major isoforms of NADPH oxidase in SEG1-EA cells. The expression of NOX5-S mRNA was significantly higher in these cells than in esophageal squamous epithelial cells. NOX5 mRNA was also significantly higher in Barrett tissues with high grade dysplasia than without dysplasia. Pulsed acid treatment significantly increased H(2)O(2) production in both SEG1-EA cells and BE mucosa, which was blocked by the NADPH oxidase inhibitor apocynin. In SEG1 cells, acid treatment increased mRNA expression of NOX5-S, but not NOX1, and knockdown of NOX5 by NOX5 small interfering RNA abolished acid-induced H(2)O(2) production. In addition, acid treatment increased intracellular Ca(2+) and phosphorylation of cAMP-response element-binding protein (CREB). Acid-induced NOX5-S expression and H(2)O(2) production were significantly inhibited by removal of extracellular Ca(2+) and by knockdown of CREB using CREB small interfering RNA. Two novel CREB-binding elements TGACGAGA and TGACGCTG were identified in the NOX5-S gene promoter. Overexpression of CREB significantly increased NOX5-S promoter activity. Knockdown of NOX5 significantly decreased [(3)H]thymidine incorporation, which was restored by 10(-13) M H(2)O(2). Knockdown of NOX5 also significantly decreased retinoblastoma protein phosphorylation and increased cell apoptosis and caspase-9 expression. In conclusion, in SEG1 EA cells NOX5-S is overexpressed and mediates acid-induced H(2)O(2) production. Acid-induced NOX5-S expression depends on an increase in intracellular Ca(2+) and activation of CREB. NOX5-S contributes to increased cell proliferation and decreased apoptosis.
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PMID:cAMP-response element-binding protein mediates acid-induced NADPH oxidase NOX5-S expression in Barrett esophageal adenocarcinoma cells. 1670 84