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)

The development of gastro-oesophageal reflux disease (GORD) is known to be a causative risk factor in the evolution of adenocarcinoma of the oesophagus. The major component of this reflux is gastric acid. However, the impact of low pH on gene expression has not been extensively studied in oesophageal cells. This study utilizes a transcriptomic and bioinformatic approach to assess regulation of gene expression in response to low pH. In more detail, oesophageal adenocarcinoma cell lines were exposed to a range of pH environments. Affymetrix microarrays were used for gene-expression analysis and results were validated using cycle limitation and real-time RT-PCR analysis, as well as northern and western blotting. Comparative promoter transcription factor binding site (TFBS) analysis (MatInspector) of hierarchically clustered gene-expression data was employed to identify the elements which may co-ordinately regulate individual gene clusters. Initial experiments demonstrated maximal induction of EGR1 gene expression at pH 6.5. Subsequent array experimentation revealed significant induction of gene expression from such functional categories as DNA damage response (EGR1-4, ATF3) and cell-cycle control (GADD34, GADD45, p57). Changes in expression of EGR1, EGR3, ATF3, MKP-1, FOSB, CTGF and CYR61 were verified in separate experiments and in a variety of oesophageal cell lines. TFBS analysis of promoters identified transcription factors that may co-ordinately regulate gene-expression clusters, Cluster 1: Oct-1, AP4R; Cluster 2: NF-kB, EGRF; Cluster 3: IKRS, AP-1F. Low pH has the ability to induce genes and pathways which can provide an environment suitable for the progression of malignancy. Further functional analysis of the genes and clusters identified in this low pH study is likely to lead to new insights into the pathogenesis and therapeutics of GORD and oesophageal cancer.
Carcinogenesis 2006 Feb
PMID:Low pH induces co-ordinate regulation of gene expression in oesophageal cells. 1611 55

The exact pathophysiologic mechanisms of esophageal cell damage and carcinogenesis by gastroesophageal reflux are not clearly understood. The aim of this study was to evaluate the damage to the esophageal epithelium that occurs after acid reflex and mixed acid and bile reflux by assessing histopathology, reactive oxygen species, and DNA damage. Eighty 10-week-old male Sprague-Dawley rats were divided into two groups, an acid reflux group and a mixed (acid/bile) reflux group. Acid reflux was achieved by esophagogastroplasty in which mixed reflux was encouraged via esophagoduodenal anastomosis. Each group contained a control subgroup that underwent sham laparotomy alone. The rats were killed 3, 6, 9, and 12 months after surgery. Malondialdehyde, protein carbonyl content, and DNA damage were determined in lymphocytes. Histopathologic analysis was performed according to the histologic activity index. Inflammation, ulcer, and regeneration in both reflux groups were significantly increased in the esophagus at 3, 6, 9, and 12 months compared with the control group. Mucosal damage was greater in the mixed reflux group compared with the gastric reflux group. Malondialdehyde and carbonyl content in the serum, and DNA damage in lymphocytes, were significantly increased in both reflux groups. At 9 and 12 months, oxidative damage was increased in the mixed reflux group compared with the acid reflux group. Oxygen-derived free radicals seem to be one of the important mediators in the evaluation and generation of reflux esophagitis. The impact of oxygen free radicals, as demonstrated in this study, can be evaluated by assessing the damage that they incur to lipid membranes, serum proteins, and circulating lymphocyte DNA. Serum malondialdehyde and carbonyl content as well as lymphocyte DNA damage were significantly increased in the setting of acid and mixed acid/bile reflux in these rodent models. Further, these serum and lymphocytic changes were associated with esophageal ulceration, inflammation, and regeneration. Evaluation of such markers as serum malondialdehyde and carbonyl content as well as evaluation of lymphocyte DNA might prove to be useful investigations in patients with precancerous and cancerous conditions in addition to conventional methods of diagnosis. Further studies, both animal and human are warranted.
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PMID:Oxidative damage in an experimentally induced gastric and gastroduodenal reflux model. 1622 42

Chronic gastroesophageal reflux disease is a known risk factor for Barrett's esophagus (BE), which induces oxidative mucosal damage. Glutathione peroxidase-3 (GPx3) is a secretory protein with potent extracellular antioxidant activity. In this study, we have investigated the mRNA and protein expression of GPx3, and explored promoter hypermethylation as an epigenetic mechanism for GPx3 gene inactivation during Barrett's carcinogenesis. Quantitative real-time reverse transcription polymerase chain reaction on 42 Barrett's adenocarcinomas (BAs) revealed consistently reduced levels of GPx3 mRNA in 91% of tumor samples. GPx3 promoter hypermethylation was detected in 62% of Barrett's metaplasia, 82% of dysplasia, and 88% of BA samples. Hypermethylation of both alleles of GPx3 was most frequently seen in BAs (P = .001). Immunohistochemical staining of GPx3 in matching tissue sections (normal, BE, Barrett's dysplasia, and BA) revealed strong immunostaining for GPx3 in normal esophageal and gastric tissues. However, weak to absent GPx3 staining was observed in Barrett's dysplasia and adenocarcinoma samples where the promoter was hypermethylated. The degree of loss of immunohistochemistry correlated with the hypermethylation pattern (monoallelic versus biallelic). The observed high frequency of promoter hypermethylation and progressive loss of GPx3 expression in BA and its associated lesions, together with its known function as a potent antioxidant, suggest that epigenetic inactivation and regulation of glutathione pathway may be critical in the development and progression of BE.
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PMID:Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis. 1622 8

The pathogenesis of cancer in Barrett's esophagus is multifactorial. Gastroesophageal reflux seems to be important in the initiation of Barrett's esophagus, but its role in promoting carcinogenesis has yet to be established. Diet, lifestyle and carcinogens, especially the nitrates, may be important in the development of carcinogenesis, and require further investigation. Inhibition of reflux-stimulated inflammatory changes, for example by inhibiting cyclooxygenase, holds promise for decreasing cancer progression. Similarly, dietary and lifestyle modification used in the management of reflux may also help to prevent the development of esophageal cancer. The molecular changes that are associated with the development of cancer in Barrett's esophagus offer several potential areas of intervention to prevent and manage esophageal cancer. Limiting cell growth, increasing apoptosis of damaged cells, limiting cell invasion and angiogenesis factors could be useful to accomplish this goal. Having a greater understanding of the pathogenesis of this condition can only help to develop more management options in the future.
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PMID:Mechanisms of disease: Carcinogenesis in Barrett's esophagus. 1626 72

Gastroesophageal reflux disease (GERD) is characterized by reflux of gastroduodenal contents, esophagitis and oxidative tissue damage in the distal esophagus. It may ultimately lead to the development of a pre-malignant Barrett's esophagus and subsequently to carcinoma. Antireflux surgery is an effective therapeutic tool to relieve GERD symptoms and to normalize the reflux to the distal esophagus. However, antireflux surgery may be insufficient to restore oxidative insult, which can promote DNA adduct formation and subsequent initiation of carcinogenesis. Controversy exists whether antireflux surgery can reverse the development of carcinoma in the mucosa. We aimed to test the effect of antireflux surgery on DNA adduct formation in the esophagus. Patients (n = 19) with objectively confirmed GERD underwent antireflux surgery and were followed up for 6 months after which a symptom evaluation, control endoscopy, biopsy and pH-measurements were performed. The amounts of DNA adducts in the proximal and distal mucosa of the esophagus were measured using the 32-P-postlabelling method. After the surgery, esophageal acid exposure was normalized in all the patients and symptoms were relieved in all but one patient. Endoscopic examinations showed that erosive esophagitis had healed in all the cases 6 months after the surgery. Barrett's esophagus was found in six cases in preoperative biopsies. The amount of DNA adducts in the distal esophagus was higher than in the proximal esophagus both pre- and postoperatively. Antireflux surgery did not change this pattern and was thus not capable of reducing DNA adduct formation. The level of DNA damage was similar in the patients having Barrett's esophagus compared to the rest of the patients. Antireflux surgery is insufficient to normalize DNA damage due to GERD. Our observations suggest that antireflux surgery is perhaps not effective in the prevention of carcinogenesis because of the persisting DNA damage.
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PMID:Antireflux surgery and esophageal mucosal DNA damage. 1628 58

A causal link between chronic inflammation and carcinogenesis is explored by reviewing illustrative examples of specific cancers and causal agents and mechanisms. The causal agents or pathologic conditions include microbial agents, gastroesophageal reflux, chronic cholecystitis and cholelithiasis, inflammatory bowel disease, and specific agents that cause chronic obstructive or diffuse interstitial lung disease. The proportion of total cancer deaths attributable to infectious agents is estimated to be about 20% to 25% in developing countries and 7% to 10% in more industrialized countries. Recurrent or persistent inflammation may induce, promote, or influence susceptibility to carcinogenesis by causing DNA damage, inciting tissue reparative proliferation, and/or creating a stromal "soil" that is enriched with cytokines and growth factors. Future research on the complex cascade of cellular and humoral factors participating in the chronic inflammatory process will further understanding of the pathogenesis of various cancers and potentially provide a rationale for targeted chemopreventive interventions.
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PMID:Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. 1651 35

Mechanisms behind the strong associations of esophageal adenocarcinoma risk with gastroesophageal reflux (GOR) and body mass remain to be defined. In a nationwide population-based case-control study, we examined associations of polymorphisms in the DNA repair genes XPD, XPC, XRCC1 and XRCC3 with risk of esophageal adenocarcinoma, squamous-cell carcinoma (SCC) and gastric cardia adenocarcinoma, and paid special attention to possible interactions with symptomatic reflux or body mass. We collected blood samples from 96, 81 and 126 interviewed incident cases of esophageal adenocarcinoma, esophageal SCC and gastric cardia adenocarcinoma, respectively, and 472 randomly selected controls, frequency-matched with regard to age and sex. DNA was extracted and polymorphisms in XPD codon 751 (Lys-->Gln), codon 312 (Asp-->Asn), C insertion in intron 10 of XPD, XPC codon 939 (Lys-->Gln), XRCC1 codon 399 (Arg-->Gln) and XRCC3 codon 241 (Thr-->Met) were examined using PCR-RFLP. Odds ratios (ORs) derived from multivariate logistic regression with adjustments for potential confounding factors estimated relative risks. XPD codon 751 Lys/Gln and Gln/Gln genotypes, compared with Lys/Lys genotype, were both associated with a more than doubled risk for esophageal adenocarcinoma (OR=2.4; 95% CI=1.4-4.4; OR=2.7, 95% CI=1.3-5.9). The combined effects of these genotypes and symptomatic GOR or body mass showed borderline significant deviation from additivity. Excess risks for esophageal SCC were also noted for XPD 751Gln variant genotypes. Other studied variants were not found to be related to the three tumors. Our study suggests that XPD 751Gln allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma.
Carcinogenesis 2006 Sep
PMID:The XPD 751Gln allele is associated with an increased risk for esophageal adenocarcinoma: a population-based case-control study in Sweden. 1657 49

Up until now, most pathophysiological concepts about gastroesophageal reflux derived from measurement of esophageal pH. However, pH monitoring does not detect all gastroesophageal reflux events, particularly when little or no acid is present in the refluxate. Esophageal impedance measurements made possible to detect and quantify all types of reflux i.e. acid, weakly acidic and non-acid reflux and to characterize the air-liquid composition of the refluxate. This new tool stimulated us to re-examine different aspects of the pathophysiology of GERD, but considering all gastroesophageal reflux events rather than only acid reflux. In this text we first analyzed gastric factors and the impact of gastric emptying on the characteristics of the refluxate. We then foccussed on the antirreflux barrier at the gastro-esophageal junction and we analysed the patterns of air and liquid reflux during transient lower esophageal sphincter relaxations (TLESRs), the most frequent mechanism for reflux in patients with GERD. With failure of the antireflux barrier, reflux occurs and we discussed in detail the air-liquid patterns, composition and proximal extent of the refluxate in normal subjects and patients with GERD both in resting and ambulatory conditions. The volume and chemical clearance mechanisms triggered after acid and non-acid reflux were characterized. The effect of esophagitis or Barrett's mucosa on electrical conductivity and impedance was analyzed as an expression of mucosal damage and increased ionic permeability. We discussed the role of non acid and gas reflux in esophageal and extraesophageal symptoms in patients with GERD. We believe that better understanding of the pathophysiology of GERD can help to characterize the relationship between gastroesophageal reflux and symptoms; the factors that determine esophageal and extraesophageal mucosal damage and/or eventual carcinogenesis related to reflux and to provide a tailored treatment to each patient targeting the individual pathophysiological defect.
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PMID:Esophageal impedance monitoring and pathophysiology of gastroesophageal reflux disease. 1679 16

Endemic cancer of the oesophagus in Africa is associated with the use of maize as the staple. In one African community endemic cancer of the oesophagus has been shown to have a strong statistical association with the consumption of foods based on maize in the meal form. A strong association with consumption of maize meal has also been shown in a region of Italy. It has been argued in the past that the association with maize consumption is due to a fortuitous association; or due to the nutritional deficiencies of maize meal; or due to fungal contamination. We argue that maize meal is a distinctly different food from whole maize, and that nutritional content as much as deficiency is responsible for predisposition of the oesophagus to carcinogenesis. An important factor is the breakdown of esterified linoleic acid to the free form in stored maize meal. This leads to excess production of prostaglandin E2 in the stomach. The excess Prostaglandin E2 causes a low-acid duodenogastro-oesophageal reflux, which predisposes to carcinogenesis. Supporting evidence is available that the steps of this mechanism occur in endemic areas, and that they are associated with the carcinogenic process. Health measures including poverty alleviation, health education, and monitoring and control of maize meal storage and content may be required to reduce the incidence of this disease in Africa.
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PMID:Maize meal predisposes to endemic squamous cancer of the oesophagus in Africa: breakdown of esterified linoleic acid to the free form in stored meal leads to increased intragastric PGE2 production and a low-acid reflux. 1682

We conducted a large population-based case-control study in Sweden to examine the association of dietary patterns and the development of cancers from the esophagus or gastroesophageal junction. In total 185 patients with esophageal adenocarcinoma, 165 with esophageal squamous-cell carcinoma, 258 with gastric cardia adenocarcinoma, and 815 randomly selected population controls underwent face-to-face interviews. Exploratory factor analysis was used to identify possible dietary patterns. Multivariate logistic regression with adjustments for age, sex, years of education, body mass index, physical activity, symptomatic gastroesophageal reflux, smoking, and total energy intake was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). We identified three major dietary patterns in this population, for example, "healthy diet" (high in vegetables, tomato, fruits, fish, and poultry), "Western diet" (high in processed meat, red meat, sweets, high-fat dairy, and high-fat gravy), and "alcohol drinker" (high in intakes of beer, liquor, and French fries). We found that a healthy diet tended to moderately decrease the risk of all three cancers under study, although none of the associations was statistically significant. A high score of Western diet was associated with increased risks of gastric cardia adenocarcinoma (high 3rd tertile vs. low 1st quartile, OR = 1.8, 95% CI = 1.1-2.9, P for trend = 0.04) and esophageal adenocarcinoma (high 3rd tertile vs. low 1st tertile, OR = 1.6, 95% CI = 0.9-3.1, P for trend = 0.13), whereas a dietary pattern characterized by high beer and liquor intake (alcohol drinker) significantly increased the risk of squamous-cell carcinoma of the esophagus (3rd tertile vs. low 1st tertile, OR = 3.5, 95% CI = 1.9-6.3, P for trend < 0.0001). Our study confirms the important role of diet in the carcinogenesis of esophageal and cardia cancer.
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PMID:Dietary patterns and risk of squamous-cell carcinoma and adenocarcinoma of the esophagus and adenocarcinoma of the gastric cardia: a population-based case-control study in Sweden. 1689 61


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