RESUMO
BACKGROUND: Vitamin D deficiency may increase esophageal cancer risk. Vitamin D affects genes regulating proliferation, apoptosis, and differentiation and induces the tumor suppressor 15-hydroxyprostaglandin dehydrogenase (PGDH) in other cancers. This nonrandomized interventional study assessed effects of vitamin D supplementation in Barrett's esophagus (BE). We hypothesized that vitamin D supplementation may have beneficial effects on gene expression including 15-PGDH in BE. METHODS: BE subjects with low grade or no dysplasia received vitamin D3 (cholecalciferol) 50,000 international units weekly plus a proton pump inhibitor for 12 weeks. Esophageal biopsies from normal plus metaplastic BE epithelium and blood samples were obtained before and after vitamin D supplementation. Serum 25-hydroxyvitamin D was measured to characterize vitamin D status. Esophageal gene expression was assessed using microarrays. RESULTS: 18 study subjects were evaluated. The baseline mean serum 25-hydroxyvitamin D level was 27 ng/mL (normal ≥30 ng/mL). After vitamin D supplementation, 25-hydroxyvitamin D levels rose significantly (median increase of 31.6 ng/mL, p<0.001). There were no significant changes in gene expression from esophageal squamous or Barrett's epithelium including 15-PGDH after supplementation. CONCLUSION: BE subjects were vitamin D insufficient. Despite improved vitamin D status with supplementation, no significant alterations in gene expression profiles were noted. If vitamin D supplementation benefits BE, a longer duration or higher dose of supplementation may be needed.
Assuntos
Esôfago de Barrett , Colecalciferol/sangue , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hidroxiprostaglandina Desidrogenases/biossíntese , Vitamina D , Idoso , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/enzimologia , Esôfago de Barrett/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacocinética , Vitamina D/administração & dosagem , Vitamina D/farmacocinéticaRESUMO
BACKGROUND & AIMS: Central adiposity is a risk factor for Barrett's esophagus (BE). Serum levels of adiponectin and leptin are deregulated in obese states and are implicated as putative mediators in the pathophysiology of esophageal columnar metaplasia. We describe associations between serum adiponectin and leptin levels with BE. METHODS: Patients were recruited prospectively for a case-control study. Fasting serum levels of adiponectin and leptin were measured in 135 patients with BE and compared with 2 separate control groups: 133 subjects with gastroesophageal reflux disease (GERD) and 1157 colon screening controls. RESULTS: Multivariate analyses adjusted for age, race, and waist-to-hip ratio showed that patients within the highest tertile of serum adiponectin level had decreased odds of BE compared with screening colonoscopy controls (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.22-0.80). This effect was more pronounced in men (OR, 0.35; 95% CI, 0.17-0.74) compared with women (OR, 0.71; 95% CI, 0.17-3.03). In comparisons of BE cases with GERD controls, subjects within the highest tertile of serum adiponectin level showed decreased odds of BE (OR, 0.65; 95% CI, 0.31-1.36), however, this was not statistically significant. Patients in the highest tertile of serum leptin level did not have a significantly increased risk of BE in comparison with GERD (OR, 1.32; 95% CI, 0.61-2.88) or screening colonoscopy controls (OR, 1.57; 95% CI, 0.82-3.04) in analyses including both sexes. Based on sex-specific analyses, sex did not significantly alter the association of leptin with odds of BE. CONCLUSIONS: Serum adiponectin was associated inversely with BE and this effect was more pronounced in men, whereas serum leptin showed no evidence of association with BE in comparisons with multiple control groups. The exact mechanism, if any, by which these adipokines promote metaplasia in the esophagus needs to be explored further.
Assuntos
Adiponectina/sangue , Esôfago de Barrett/patologia , Leptina/sangue , Soro/química , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
BACKGROUND: Antimicrobial peptides (AMPs) maintain a sterile environment in intestinal crypts, limiting microbial colonization and invasion. Decreased AMP expression is proposed to increase the risk for inflammatory bowel disease. Expression and function of inducible AMPs, human ß-defensin 2 and 3 (hBD-2 and hBD-3), remain poorly characterized in healthy and chronically inflamed intestine. METHODS: Peptide concentrations of hBD-2 and hBD-3 in serum and intestinal biopsies of subjects with ulcerative colitis and Crohn's disease (CD), and those of healthy subjects were measured by ELISA. Messenger RNA of hBD-2 and hBD-3 was quantified by quantitative PCR in biopsies from the terminal ileum (TI) of patients with CD and healthy controls. Peptide localization of hBD-3 in the TI was visualized by confocal microscopy. RESULTS: Immunoreactive hBD-3 peptide is present in the TI and colon in healthy subjects. In the TI of patients with CD, hBD-3, but not hBD-2 peptide, is increased 4-fold, whereas hBD-2 peptide is elevated in the serum. Messenger RNA of hBD-3 in the CD TI remains unchanged and does not correlate with hBD-3 peptide expression. However, hBD-3 is localized to Paneth cell granules and the apical surface of the healthy columnar epithelium. In CD, hBD-3 peptide location switches to the basolateral surface of the columnar epithelium and is diffusely distributed within the lamina propria. CONCLUSION: The peptide hBD-3 throughout the healthy gastrointestinal tract suggests a role in maintaining balance between host defenses and commensal microbiota. Increased and relocalized secretion of hBD-3 toward the lamina propria in the CD TI indicates possible local immunomodulation during chronic inflammation, whereas increased serum hBD-2 in CD implicates its systemic antimicrobial and immunomodulatory role.
Assuntos
Doença de Crohn/metabolismo , Trato Gastrointestinal/metabolismo , Ileíte/metabolismo , Celulas de Paneth/metabolismo , Fragmentos de Peptídeos/metabolismo , beta-Defensinas/metabolismo , Western Blotting , Estudos de Casos e Controles , Doença de Crohn/genética , Doença de Crohn/patologia , Ensaio de Imunoadsorção Enzimática , Humanos , Ileíte/genética , Ileíte/patologia , Técnicas Imunoenzimáticas , Inflamação/metabolismo , Inflamação/patologia , Mucosa Intestinal/metabolismo , Intestinos/patologia , Fragmentos de Peptídeos/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , beta-Defensinas/genéticaRESUMO
There is a critical need to identify molecular markers that can reliably aid in stratifying esophageal adenocarcinoma (EAC) risk in patients with Barrett's esophagus. MicroRNAs (miRNA/miR) are one such class of biomolecules. In the present cross-sectional study, we characterized miRNA alterations in progressive stages of neoplastic development, i.e., metaplasia-dysplasia-adenocarcinoma, with an aim to identify candidate miRNAs potentially associated with progression. Using next generation sequencing (NGS) as an agnostic discovery platform, followed by quantitative real-time PCR (qPCR) validation in a total of 20 EACs, we identified 26 miRNAs that are highly and frequently deregulated in EACs (≥ 4-fold in >50% of cases) when compared to paired normal esophageal squamous (nSQ) tissue. We then assessed the 26 EAC-derived miRNAs in laser microdissected biopsy pairs of Barrett's metaplasia (BM)/nSQ (n = 15), and high-grade dysplasia (HGD)/nSQ (n = 14) by qPCR, to map the timing of deregulation during progression from BM to HGD and to EAC. We found that 23 of the 26 candidate miRNAs were deregulated at the earliest step, BM, and therefore noninformative as molecular markers of progression. Two miRNAs, miR-31 and -31*, however, showed frequent downregulation only in HGD and EAC cases suggesting association with transition from BM to HGD. A third miRNA, miR-375, showed marked downregulation exclusively in EACs and in none of the BM or HGD lesions, suggesting its association with progression to invasive carcinoma. Taken together, we propose miR-31 and -375 as novel candidate microRNAs specifically associated with early- and late-stage malignant progression, respectively, in Barrett's esophagus.
Assuntos
Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Transformação Celular Neoplásica/genética , MicroRNAs/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Progressão da Doença , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaplasia/genética , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
BACKGROUND: It is postulated that high serum levels of insulin and insulin growth factor 1 (IGF-1) mediate obesity-associated carcinogenesis. The relationship of insulin, IGF-1 and IGF binding proteins (IGFBP) with Barrett's oesophagus (BO) has not been well examined. METHODS: Serum levels of insulin and IGFBPs in patients with BO were compared with two separate control groups: subjects with gastro-oesophageal reflux disease (GORD) and screening colonoscopy controls. Fasting insulin, IGF-1 and IGFBPs were assayed in the serum of BO cases (n = 135), GORD (n = 135) and screening colonoscopy (n = 932) controls recruited prospectively at two academic hospitals. Logistic regression was used to estimate the risk of BO. RESULTS: Patients in the highest tertile of serum insulin levels had an increased risk of BO compared with colonoscopy controls (adjusted OR 2.02, 95% CI 1.15 to 3.54) but not compared with GORD controls (adjusted OR 1.55, 95% CI 0.76 to 3.15). Serum IGF-1 levels in the highest tertile were associated with an increased risk of BO (adjusted OR 4.05, 95% CI 2.01 to 8.17) compared with the screening colonoscopy control group but were not significantly different from the GORD control group (adjusted OR 0.57, 95% CI 0.27 to 1.17). IGFBP-1 levels in the highest tertile were inversely associated with a risk of BO in comparison with the screening colonoscopy controls (adjusted OR 0.11, 95% CI 0.05 to 0.24) but were not significantly different from the GORD control group (adjusted OR 1.04, 95% CI 0.49 to 2.16). IGFBP-3 levels in the highest tertile were inversely associated with the risk of BO compared with the GORD controls (OR 0.36, 95% CI 0.16 to 0.81) and also when compared with the colonoscopy controls (OR 0.40, 95% CI 0.20 to 0.79). CONCLUSIONS: These results provide support for the hypothesis that the insulin/IGF signalling pathways have a role in the development of BO.