Vitamin D Receptor as a Potential Gene Therapy Target in Barrett's Esophagus and Esophageal Adenocarcinoma

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Rok publikování 2017
Druh Vyžádané přednášky
Popis Background: Gastroesophageal reflux disease (GERD) significantly increases the risk of reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). While expression of vitamin D receptor (VDR) decreases during oncogenesis in some tissues, higher levels of VDR mRNA were found in esophageal tissue in patients with BE and EAC compared to normal esophageal squamous epithelium. The aim of present study was to test the hypothesis based on our pilot study of the VDR gene variability that VDR is a potential predictive marker and gene therapy target in BE and EAC. Methods: Totally, 445 subjects were included in this case control study: 129 healthy, 108 patients with non-erosive gastroesophageal reflux disease (NERD), 139 with RE, 57 with BE and 12 with EAC. GERD was diagnosed based on the clinical symptoms such as heartburn (pyrosis) and/or acid regurgitation and objectified with 24-h pH-metry, esophagogastroduodenoscopy and manometry. All patients were genotyped for the VDR gene profile. In randomly selected subgroups of subjects (10 with RE, 17 with BE and 6 with EAC), the VDR levels in bioptic esophageal tissue samples (paraffin-embedded tissue) were immunohistochemically examined using antibodies to VDR (ab134826, Abcam). Results: The significant differences between the VDR levels in the nuclei of pathological tissue vs. normal tissue in patients with BE (P=0.01) were found. Higher VDR levels were observed in the nuclei than in the cytoplasm in the pathological tissue of patients with RE (P<0.01), with EAC (P<0.05) and marginally in patients with BE (P=0.065). In addition, higher levels of the VDR protein in the nuclei than in the cytoplasm were also measured in the “normal” (mostly with inflammatory changes) tissue of patients with EAC (P<0.05). No differences in the VDR protein levels in esophageal tissue were found after the stratification of samples according to the patient´s VDR gene profile. However, the specific VDR gene profile was found as a protective factor for BE and EAC development in GERD patients (P<0.05). Probably due to a small number of carriers with a minor frequent allele, the VDR protein levels in esophageal tissue were comparable between the samples after their stratification according to the patient´s VDR gene profile. Nevertheless, a functional significance of the gene variant associated with BE and EAC and its protective potential is known. Conclusion: VDR plays a significant role in the pathogenesis of GERD. We suggest that the VDR gene profile can be a useful predictive factor for optimizing algorithm for secondary prevention measures in the development of the BE and EAC in patients with GERD. VDR seems to be suitable target for gene therapy in patients with BE and EAC. Acknowledgements: The study was supported by grant GACR GB14-37368G, project MUNI/A/0948/2016 and funds from the Faculty of Medicine MU to junior researcher Petra Borilova Linhartova.
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