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)

MUC4 (mucin 4) is a membrane-bound mucin overexpressed in the early steps of oesophageal carcinogenesis and implicated in tumour progression. We previously showed that bile acids, main components of gastro-oesophageal reflux and tumour promoters, up-regulate MUC4 expression [Mariette, Perrais, Leteurtre, Jonckheere, Hemon, Pigny, Batra, Aubert, Triboulet and Van Seuningen (2004) Biochem. J. 377, 701-708]. HNF (hepatocyte nuclear factor) 1alpha and HNF4alpha transcription factors are known to mediate bile acid effects, and we previously identified cis-elements for these factors in MUC4 distal promoter. Our aim was to demonstrate that these two transcription factors were directly involved in MUC4 activation by bile acids. MUC4, HNF1alpha and HNF4alpha expressions were evaluated by immunohistochemistry in human oesophageal tissues. Our results indicate that MUC4, HNF1alpha and HNF4alpha were co-expressed in oesophageal metaplastic and adenocarcinomatous tissues. Studies at the mRNA, promoter and protein levels indicated that HNF1alpha regulates endogenous MUC4 expression by binding to two cognate cis-elements respectively located at -3332/-3327 and -3040/-3028 in the distal promoter. We also showed by siRNA (small interfering RNA) approach, co-transfection and site-directed mutagenesis that HNF1alpha mediates taurodeoxycholic and taurochenodeoxycholic bile acid activation of endogenous MUC4 expression and transcription in a dose-dependent manner. In conclusion, these results describe a new mechanism of regulation of MUC4 expression by bile acids, in which HNF1alpha is a key mediator. These results bring new insights into MUC4 up-regulation in oesophageal carcinoma associated with bile reflux.
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PMID:Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. 1703 83

Barrett's esophagus (BE) is an acquired condition in which the normal squamous epithelium in the distal esophagus is replaced by a metaplastic columnar epithelium, as a complication of chronic gastroesophageal reflux. The clinical significance of this disease is its associated predisposition to esophageal adenocarcinoma (EAC). Recently, and similarly to other human malignancies, the Wnt signaling pathway and its key component beta-catenin have been implicated in the carcinogenesis of BE. Although mutations in adenomatous polyposis coli (APC) or beta-catenin are rare in EAC, alterations of upstream components, such as overexpression of Wnt2 ligand or downregulation of Wnt antagonists may play dominant roles in the activation of the Wnt pathway. Increasing evidence suggests that inhibiting the Wnt pathway may be a new targeted therapy for the treatment of cancers and could, therefore, be promising for the cure of EAC, which remains a highly lethal disease.
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PMID:Targeting the Wnt signaling pathway to treat Barrett's esophagus. 1729 95

Squamous cell carcinoma (SCC) of the human esophagus has a multifactorial etiology involving several environmental and/or genetic factors. Recently, gastroesophageal reflux has been implicated as a causative factor in upper aerodigestive tract carcinogenesis. The development of esophageal squamous cell carcinoma (ESCC) in a duodenal contents reflux model without any known carcinogen present has been reported previously. In this study, the duodenal contents reflux model without gastrectomy was used. At 60 weeks post-operatively, all surviving animals had malignant lesions as follows: ESCC (40%), esophageal adenocarcinoma (EAC) (20%) and adenosquamous carcinoma (40%). In one subject, a well-differentiated ESCC was detected with thoracic dissemination and metastases in lymph nodes. A novel cell line, designated ESCC-DR, was established from the thoracic metastatic tumor at the 60th post-operative week. These cells were transplanted into nude mice, and the developed nodules represented a well differentiated ESCC, resembling that of the parent site. Duodenal contents reflux has a great potential for malignant initiation and plays a role in developing not only EAC but also ESCC.
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PMID:Association between duodenal contents reflux and squamous cell carcinoma--establishment of an esophageal cancer cell line derived from the metastatic tumor in a rat reflux model. 1735 29

Recent clinical data have revealed that mixed reflux (MR) of gastric acid and duodenal contents frequently occurs in patients with gastroesophageal reflux disease and a progressive increase of MR occurs with increasing severity across gastroesophageal reflux disease. Herein we report a novel rat surgical model in which esophageal metaplasia and adenocarcinoma develop as complications of MR. The model was created by performing an esophagojejunostomy and a gastrojejunostomy 5 mm proximal to the esophagojejunal anastomosis in 40 rats. Severe inflammatory and proliferative changes, high prevalence of esophageal metaplasia (78%), and adenocarcinoma (50%) were observed in the lower part of the esophagus of rats 20 weeks after surgery. The resulting esophageal lesions resembled those described in humans and supported a progression from intestinal metaplasia to dysplasia and, ultimately, esophageal adenocarcinoma. Such a model may provide a useful tool in study of human reflux-induced carcinogenesis.
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PMID:A rat surgical model of esophageal metaplasia and adenocarcinoma-induced by mixed reflux of gastric acid and duodenal contents. 1739 26

The mechanism of esophageal mucosal injury has gradually been understood at the microbiological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines, leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). Our present study reveals that expression of IL-8 mRNA, a potent neutrophil chemotactic and activating peptide, is correlated with the endoscopic grade of esophagitis or with inflammatory cell infiltration. In addition, it has been shown that bile acids and trypsin can promote IL-8 production from human esophageal epithelial cells via NFkappaB-and AP-1-dependent mechanism. Nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and neuropeptides such as substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with antiinflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.
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PMID:[Cytokine expression in GERD]. 1751 Dec 18

Obesity and gastro-oesophageal reflux are the main predisposing factors for oesophageal adenocarcinoma. We have examined the effects of transient acid exposure and leptin on OE33 oesophageal adenocarcinoma cells. Leptin and acid individually stimulated proliferation and inhibited apoptosis and the combination was synergistic. Leptin receptor protein levels were unchanged by acid exposure. The COX-2 inhibitor NS 398 blocked the effects of acid and leptin but while both acid and leptin individually significantly increased PGE2 production and COX-2 mRNA levels, the combination was not more effective than either stimulant alone. Leptin synergistically enhanced acid-stimulated EGFR and ERK phosphorylation but did not further increase JNK or p38 MAP kinase phosphorylation. Specific EGFR and ERK inhibitors reduced the effects of leptin and acid alone and in combination. The combination of increased circulating leptin levels in obesity and transient reflux of gastric acid may promote oesophageal carcinogenesis by increasing proliferation and inhibiting apoptosis.
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PMID:Leptin synergistically enhances the anti-apoptotic and growth-promoting effects of acid in OE33 oesophageal adenocarcinoma cells in culture. 1761 45

Bile reflux may play a key role for esophageal carcinogenesis in reflux disease. In search for bile-specific effects, the animal model of esophageal cancer was applied in a mutagenesis assay. Big Blue transgenic mice were operated with microsurgical techniques. Seven had total gastrectomy with esophagojejunostomy creating esophageal reflux of bile and five had a sham operation. After 24 weeks, the mutation frequency (MF) was measured through standard Big Blue mutagenesis assay in the esophageal mucosa and the duodenum as control. Esophageal reflux resulted in esophagitis in the distal esophagus. The MF in esophageal mucosa was 1.6 times higher in animals with reflux than in sham-operated animals; it was identical in the duodenum. In conclusion, the mutagenic potential of bile reflux has been confirmed. However, mechanisms of carcinogenesis in the esophageal cancer model other than chronic inflammation could not be identified because of the only moderately increased MF.
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PMID:Carcinogenesis in reflux disease--in search for bile-specific effects. 1792 60

The incidence of esophageal adenocarcinoma has increased in recent years, and Barrett's esophagus is a recognized risk factor. Gastroesophageal reflux of acid and/or bile is linked to these conditions and to reflux esophagitis. Inflammatory disorders can lead to carcinogenesis through activation of "prosurvival genes," including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Increased expression of these enzymes has been found in esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Polymorphic variants in COX-2 and iNOS genes may be modifiers of risk of these conditions. In a population-based case-control study, we examined associations of the COX-2 8473 T>C and iNOS Ser(608) Leu (C>T) polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), and reflux esophagitis (n = 230) and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. The presence of at least one COX-2 8473 C allele was associated with a significantly increased risk of esophageal adenocarcinoma (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.40). There was no significant association between this polymorphism and risk of Barrett's esophagus or reflux esophagitis or between the iNOS Ser 608 Leu polymorphism and risk of these esophageal conditions. Our study suggests that the COX-2 8473 C allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma.
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PMID:Cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphisms and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. 1834 95

Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid-induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving I kappaB kinases beta (IKK beta), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKK beta inhibitor Bay 11-7082 suppressed bile acid-induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKK beta (pIKK beta) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKK beta expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKK beta signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus-associated EAC.
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PMID:Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in Barrett's-associated esophageal adenocarcinoma. 1841 30

The etiology of esophageal mucosal injury is complex, since it may involve the reflux of gastric acid, bile acid, and pancreatic juice, external factors such as drugs and alcohol, or functional factors such as esophagogastric motility. The mechanism of esophageal mucosal injury has gradually been understood at the molecular biological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines (interleukin-6 and -8), leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). In addition, nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with anti-inflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.
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PMID:Inflammation and oxidative stress in gastroesophageal reflux disease. 1843 9


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