|
1
|
Aggeletopoulou I, Konstantakis C, Triantos C. Chronic Atrophic Autoimmune Gastritis: The Evolving Role of Vitamin D. FRONT BIOSCI-LANDMRK 2024; 29:252. [PMID: 39082343 DOI: 10.31083/j.fbl2907252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 01/06/2025]
Abstract
Vitamin D possesses a crucial role in preserving bone health, modulating the immune system responses, and supporting various physiological functions throughout the body. Chronic atrophic autoimmune gastritis (CAAG) constitutes an autoimmune condition marked by inflammation and damage to the stomach cells, often resulting in a decreased ability to absorb certain nutrients, including vitamin B12 and iron. Although, vitamin D is not directly affected by this condition, the sufficiency of this micronutrient seems to have important implications for overall health and management of the disease. The aim of the current review was to assess the incidence and related features of vitamin D deficiency in patients with CAAG and to elucidate the complex regulatory role of this nutrient, in an effort to improve patient outcomes. Vitamin D greatly contributes to the regulation of the immune system. In patients with CAAG, the immune system attacks the stomach lining; thus, the maintenance of a healthy and balanced immune response is important. In autoimmune conditions such as CAAG, where inflammation plays a decisive role in disease progression, vitamin D could potentially exert a role in managing and controlling the associated symptoms. Adequate vitamin D levels may help in regulating the immune response and reducing inflammation. In addition, patients with CAAG are at risk of nutrient deficiencies, including vitamin B12 and iron, which can lead to anemia and bone health issues. As vitamin D is critical for calcium absorption and bone health, assurance of sufficient levels of this micronutrient can be beneficial in preventing or mitigating bone-related complications. In conclusion, regular monitoring of vitamin D levels, among other nutrients, and appropriate supplementation, when necessary, can help improve overall health and well-being in these patients.
Collapse
Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
| |
Collapse
|
|
2
|
Shang QX, Yang YS, Zhang HL, Cheng YP, Lu H, Yuan Y, Chen LQ, Ji AF. Vitamin D receptor induces oxidative stress to promote esophageal squamous cell carcinoma proliferation via the p53 signaling pathway. Heliyon 2024; 10:e23832. [PMID: 38234882 PMCID: PMC10792188 DOI: 10.1016/j.heliyon.2023.e23832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 12/05/2023] [Accepted: 12/13/2023] [Indexed: 01/19/2024] Open
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is a common pathological esophageal cancer with poor prognosis. Vitamin D deficiency reportedly occurs in ESCC patients, and this is related to single nucleotide polymorphism of vitamin D receptor (VDR). Objective We investigated the effect of VDR on ESCC proliferation, invasion, and metastasis and its potential mechanism. Methods ESCC and normal tissues were collected from 20 ESCC patients. The ESCC tissue microarray contained 116 pairs of ESCC and normal tissues and 73 single ESCC tissues. VDR expression and its clinicopathological role were determined by real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry staining. sh-VDR and VDR overexpression were used to validate the effect of VDR on ESCC cell phenotype, and tandem mass tag-based quantitative proteomics and bioinformatics methods identified differential VDR-related proteins. The downstream pathway and regulatory effect were analyzed using ingenuity pathway analysis (IPA). Differentially expressed proteins were verified through parallel reaction monitoring and Western blot. In vivo imaging visualized subcutaneous tumor growth following tail vein injection of VDR-deficient ESCC cells. Results High VDR expression was observed in ESCC tissues and cells. Gender, T stage, and TNM stage were related to VDR expression, which was the independent prognostic factor related to ESCC. VDR downregulation repressed ESCC cell proliferation, invasion, and migration in vitro and subcutaneous tumor growth and lung metastases in vivo. The cell phenotype changes were reversed upon VDR upregulation, and differential proteins were mainly enriched in the p53 signaling pathway. TP53 cooperated with ABCG2, APOE, FTH1, GCLM, GPX1, HMOX1, JUN, PRDX5, and SOD2 and may activate apoptosis and inhibit oxidative stress, cell metastasis, and proliferation. TP53 was upregulated after VDR knockdown, and TP53 downregulation reversed VDR knockdown-induced cell phenotype changes. Conclusions VDR may inhibit p53 signaling pathway activation and induce ESCC proliferation, invasion, and metastasis by activating oxidative stress.
Collapse
Affiliation(s)
- Qi-Xin Shang
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yu-Shang Yang
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Han-Lu Zhang
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ya-Ping Cheng
- Heping Hospital Affiliated to Changzhi Medical University, No. 161 Jiefang East Street, Changzhi, 046000, China
| | - Han Lu
- Heping Hospital Affiliated to Changzhi Medical University, No. 161 Jiefang East Street, Changzhi, 046000, China
| | - Yong Yuan
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Long-Qi Chen
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ai-Fang Ji
- Heping Hospital Affiliated to Changzhi Medical University, No. 161 Jiefang East Street, Changzhi, 046000, China
| |
Collapse
|
|
3
|
Mejza M, Małecka-Wojciesko E. Diagnosis and Management of Barrett's Esophagus. J Clin Med 2023; 12:jcm12062141. [PMID: 36983142 PMCID: PMC10057256 DOI: 10.3390/jcm12062141] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/07/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Barrett's esophagus is a metaplastic change of esophageal mucosa, which can be characterized by its salmon-colored lining and the presence of columnar epithelium with goblet cells. It is a well-established precancerous state of esophageal adenocarcinoma, a tumor with very poor survival rates, which incidence is rapidly growing. Despite numerous research, the debate about its diagnosis and management is still ongoing. This article aims to provide an overview of the current recommendations and new discoveries regarding the subject.
Collapse
Affiliation(s)
- Maja Mejza
- Department of Digestive Tract Diseases, Medical University, 90-153 Lodz, Poland
| | | |
Collapse
|
|
4
|
Jayaprakash S, Hegde M, Girisa S, Alqahtani MS, Abbas M, Lee EHC, Yap KCH, Sethi G, Kumar AP, Kunnumakkara AB. Demystifying the Functional Role of Nuclear Receptors in Esophageal Cancer. Int J Mol Sci 2022; 23:ijms231810952. [PMID: 36142861 PMCID: PMC9501100 DOI: 10.3390/ijms231810952] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/14/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Esophageal cancer (EC), an aggressive and poorly understood disease, is one of the top causes of cancer-related fatalities. GLOBOCAN 2020 reports that there are 544,076 deaths and 604,100 new cases expected worldwide. Even though there are various advancements in treatment procedures, this cancer has been reported as one of the most difficult cancers to cure, and to increase patient survival; treatment targets still need to be established. Nuclear receptors (NRs) are a type of transcription factor, which has a key role in several biological processes such as reproduction, development, cellular differentiation, stress response, immunity, metabolism, lipids, and drugs, and are essential regulators of several diseases, including cancer. Numerous studies have demonstrated the importance of NRs in tumor immunology and proved the well-known roles of multiple NRs in modulating proliferation, differentiation, and apoptosis. There are surplus of studies conducted on NRs and their implications in EC, but only a few studies have demonstrated the diagnostic and prognostic potential of NRs. Therefore, there is still a paucity of the role of NRs and different ways to target them in EC cells to stop them from spreading malignancy. This review emphasizes the significance of NRs in EC by discussing their diverse agonists as well as antagonists and their response to tumor progression. Additionally, we emphasize NRs’ potential to serve as a novel therapeutic target and their capacity to treat and prevent EC.
Collapse
Affiliation(s)
- Sujitha Jayaprakash
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - E. Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Kenneth Chun-Hong Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Correspondence: (A.P.K.); (A.B.K.)
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
- Correspondence: (A.P.K.); (A.B.K.)
| |
Collapse
|
|
5
|
Ali II, Shah I, Marzouk S, Karam SM, Al Menhali A. Vitamin D Is Necessary for Murine Gastric Epithelial Homeostasis. BIOLOGY 2021; 10:705. [PMID: 34439938 PMCID: PMC8389223 DOI: 10.3390/biology10080705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/20/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023]
Abstract
Unlike other organs, the importance of VD in a normal stomach is unknown. This study focuses on understanding the physiological role of vitamin D in gastric epithelial homeostasis. C57BL/6J mice were divided into three groups that were either fed a standard diet and kept in normal light/dark cycles (SDL), fed a standard diet but kept in the dark (SDD) or fed a vitamin D-deficient diet and kept in the dark (VDD). After 3 months, sera were collected to measure vitamin D levels by LC-MS/MS, gastric tissues were collected for immunohistochemical and gene expression analyses and gastric contents were collected to measure acid levels. The VDD group showed a significant decrease in the acid-secreting parietal cell-specific genes Atp4a and Atp4b when compared with the controls. This reduction was associated with an increased expression of an antral gastrin hormone. VDD gastric tissues also showed a high proliferation rate compared with SDL and SDD using an anti-BrdU antibody. This study indicates the requirement for normal vitamin D levels for proper parietal cell functions.
Collapse
Affiliation(s)
- Ifrah Ismail Ali
- Department of Biology, College of Science, United Arab Emirates University, Al Ain 15551, United Arab Emirates;
| | - Iltaf Shah
- Department of Chemistry, College of Science, United Arab Emirates University, Al Ain 15551, United Arab Emirates; (I.S.); (S.M.)
| | - Sayed Marzouk
- Department of Chemistry, College of Science, United Arab Emirates University, Al Ain 15551, United Arab Emirates; (I.S.); (S.M.)
| | - Sherif M. Karam
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates;
| | - Asma Al Menhali
- Department of Biology, College of Science, United Arab Emirates University, Al Ain 15551, United Arab Emirates;
| |
Collapse
|
|
6
|
Thiruvengadam SK, Tieu AH, Luber B, Wang H, Meltzer SJ. Risk Factors for Progression of Barrett's Esophagus to High Grade Dysplasia and Esophageal Adenocarcinoma. Sci Rep 2020; 10:4899. [PMID: 32184470 PMCID: PMC7078316 DOI: 10.1038/s41598-020-61874-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 03/01/2020] [Indexed: 12/17/2022] Open
Abstract
Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC). Methods of identifying BE patients at high risk for progression to high-grade dysplasia (HGD) or EAC are needed to improve outcomes and identify who will benefit most from intensive surveillance or ablative therapy. Clinical predictors of BE progression to HGD or EAC are poorly understood, with multiple contradictory studies. We performed a retrospective study which included 460 patients at Johns Hopkins Hospital who underwent at least 2 upper endoscopies 6 months apart showing biopsy-documented BE between 1992 and 2013. Patients with EAC or HGD at the initial endoscopy were excluded. Demographic, clinicopathological, and endoscopic data were collected. Univariate and multivariate Cox proportional hazards analyses with time to progression to HGD and EAC were performed. Among 460 patients included in the study, 132 BE patients developed HGD and 62 developed EAC. Significant EAC risk factors included age, abdominal obesity, caffeine intake, and the presence of HGD. Risk factors for HGD or EAC included age, caffeine intake, and low-grade dysplasia while colonic adenomas trended towards significance. Notably, a history of statin or SSRI usage reduced the risk of EAC or HGD by 49% or 61%, respectively. Our study validated several known and identified several novel risk factors, including a history of colonic adenomas or caffeine usage. Low-grade dysplasia was a risk factor for progression but various endoscopic characteristics were not, suggesting that screening strategies should focus on histology instead. We identified SSRIs as a new potentially chemoprotective medication.
Collapse
Affiliation(s)
| | - Alan H Tieu
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Division of Gastroenterology and Hepatology, Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Brandon Luber
- Division of Bioinformatics and Biostatistics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Hao Wang
- Division of Bioinformatics and Biostatistics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Stephen J Meltzer
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| |
Collapse
|
|
7
|
Shen K, Zhang S, Ma S, Zhang H. Molecular Markers and Diagnostic Model Specific for Barrett's Esophagus. J Comput Biol 2019; 26:1367-1378. [PMID: 31259619 DOI: 10.1089/cmb.2019.0064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Biomarkers involved in the progression of Barrett's esophagus (BE) have not been extensively studied. We aimed to identify novel molecular markers for the early diagnosis of BE. The expression profiles of GSE100843 including BE segment and normal squamous mucosa samples before and after vitamin D3 supplementation were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified using the limma package. Principal component analysis was performed using Minitab, and DEGs in the top three principal components were clustered into different gene sets by the mclust package. Pathways and functions enriched by these gene sets were evaluated by deregulation score analysis. Key genes associated with BE were identified by coexpression analysis and a genetic algorithm. Using the xgboost package, an XGBoost classifier specific for BE was further constructed based on the key genes. A total of 2598 DEGs were identified, which were further clustered into nine gene sets. According to the deregulation scores of pathways and functions enriched by these gene sets, nine functional and pathway terms were significantly deregulated in BE. Among the DEGs, CREB3L1, HNF1B, and IL35 were genes with high fitness levels and connectivity degrees, predicting that they were key genes associated with BE. The XGBoost classifier constructed using the key genes was efficient and robust in BE prediction. The accuracies for prediction were 93% and 87% for training and validation datasets, respectively. Key genes may serve as novel biomarkers of BE, and the XGBoost classifier may contribute to the diagnosis of BE in future clinical practice.
Collapse
Affiliation(s)
- Kexin Shen
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Shujuan Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Shurong Ma
- Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Haishan Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
8
|
Goyal H, Perisetti A, Rahman MR, Levin A, Lippi G. Vitamin D and Gastrointestinal Cancers: A Narrative Review. Dig Dis Sci 2019; 64:1098-1109. [PMID: 30511197 DOI: 10.1007/s10620-018-5400-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 11/27/2018] [Indexed: 12/14/2022]
Abstract
Calcitriol (1,25(OH)2D3) performs various activities throughout the body. Although low serum 25-hydroxyvitamin D [25(OH)D] levels are associated with several disease processes such as risk of fractures and falls, hypertension, cardiovascular disease, and diabetes mellitus, recent evidence attests that this important hormone also regulates several cellular pathways involved in cancer development and progression. Calcitriol modulates several genes controlling gut physiology and calcium homeostasis and also maintains the integrity of epithelial barriers, regulates the absorption of phosphate and calcium, and modulates host defense against pathogens and inflammatory response by interplaying with several types of secretory and immune cells. Vitamin D deficiency is significantly related to increased risk of developing certain types of cancer. This deficiency can be prevented by vitamin D supplementation which is both economical and safe. This can lower the risk of developing cancer and also improve the prognosis of patients with gastrointestinal malignancy, but epidemiological data remain inconsistent. Several retrospective observational studies have demonstrated the benefits of vitamin D supplementation, but a few randomized controlled trials have not seemingly supported the beneficial role of vitamin D supplementation in gastrointestinal cancers. Therefore, in this literature review, we aimed to examine the possible role of vitamin D in gastrointestinal malignancies, including gastric, esophageal, pancreatic, hepatic, and colorectal cancers.
Collapse
Affiliation(s)
- Hemant Goyal
- Mercer University School of Medicine, 707 Pine St, Macon, GA, 31201, USA.
| | - Abhilash Perisetti
- University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA
| | - M Rubayat Rahman
- University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA
| | - Avi Levin
- Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA
| | - Giuseppe Lippi
- Section of Clinical Biochemistry, University of Verona, Verona, Italy
| |
Collapse
|
|
9
|
McCain S, Trainor J, McManus DT, McMenamin ÚC, McQuaid S, Bingham V, James JA, Salto-Tellez M, Turkington RC, Coleman HG. Vitamin D receptor as a marker of prognosis in oesophageal adenocarcinoma: a prospective cohort study. Oncotarget 2018; 9:34347-34356. [PMID: 30344947 PMCID: PMC6188147 DOI: 10.18632/oncotarget.26151] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 09/05/2018] [Indexed: 12/14/2022] Open
Abstract
AIMS Vitamin D receptor (VDR) expression has been associated with survival in several cancer sites. This study aims to evaluate the association between VDR expression and prognosis in oesophageal adenocarcinoma patients. RESULTS During a median of 2.5 (maximum 9) years of follow-up, 75 patients died. In analysis adjusted for confounders, higher VDR expression was associated with an improved overall survival (HR 0.49 95% CI 0.25-0.96) and disease-specific survival (HR 0.50 95% CI 0.26-0.99), when comparing the highest with the lowest tertile of expression. These associations were strongest in sensitivity analysis restricted to junctional tumours. CONCLUSIONS This study is the first to demonstrate that patients with higher VDR expression in oesophageal adenocarcinoma have a more favourable prognosis. Further work is needed to validate these findings, and to define the role of VDR in the aetiology, progression and management of oesophageal adenocarcinoma. METHODS Oesophageal adenocarcinoma specimens and clinical data were collected from 130 patients treated with neo-adjuvant chemotherapy prior to surgical resection at the Northern Ireland Cancer Centre between 2004 and 2012. Tissue microarrays were created and immunohistochemical staining for VDR was performed on triplicate tumour cores from each resection specimen. Cox proportional hazards models were applied to evaluate associations between VDR, according to tertiles of expression, and survival outcomes.
Collapse
Affiliation(s)
- Stephen McCain
- Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland
| | - James Trainor
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland
| | - Damian T. McManus
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland
| | - Úna C. McMenamin
- Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland
| | - Stephen McQuaid
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland
| | - Victoria Bingham
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland
| | - Jacqueline A. James
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland
| | - Manuel Salto-Tellez
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland
| | - Richard C. Turkington
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland
| | - Helen G. Coleman
- Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland
| |
Collapse
|
|
10
|
Singhal S, Kapoor H, Subramanian S, Agrawal DK, Mittal SK. Polymorphisms of Genes Related to Function and Metabolism of Vitamin D in Esophageal Adenocarcinoma. J Gastrointest Cancer 2018; 50:867-878. [PMID: 30187205 DOI: 10.1007/s12029-018-0164-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The vitamin D receptor (VDR) endocrine system has emerged as an endogenous pleiotropic biological cell regulator with anti-neoplastic effects on breast, colorectal, and prostatic adenocarcinomas. We studied the association of gene expression, polymorphisms of VDR, CYP27B1, and CYP24A1 genes and serum vitamin D levels as surrogate markers of disease progression in patients with acid reflux, Barrett's esophagus (BE), or esophageal adenocarcinoma (EAC). METHODS We analyzed blood and tissue samples from patients with biopsy-confirmed BE or EAC for vitamin D levels, gene expressions, and polymorphisms in VDR (FokI [F/f], BsmI [B/b], ApaI [A/a], and TaqI [T/t]), CYP27B1 (HinfI [H/h]), and CYP24A1 (Hpy1881 [Y/y]). Percentages of homozygous dominant/recessive or heterozygous traits were assessed for each polymorphism in all patient subgroups. RESULTS Genomic Bb and FF polymorphisms were highly prevalent in EAC patients, whereas BE patients had a high prevalence of wild-type Hpy1881 (YY polymorphism). Some polymorphisms (Yy for CYP24A1, bb for VDR) were noted only in EAC patients. Yy and bb forms were both uniquely present in some EAC patients without associated Barrett's lesions, but not in patients with concomitant BE. AA and bb polymorphisms were associated with decreased response to neoadjuvant therapy. A high level of VDR and CYP24A1 mRNA expression was observed in EAC tissue of non-responders. Serum vitamin D deficiency was common in EAC patients. CONCLUSIONS Specific polymorphisms in vitamin D metabolism-related genes are associated with the likelihood of reflux-BE-EAC progression. Identifying such polymorphisms may aid in development of better surveillance and diagnostic and therapeutic protocols.
Collapse
Affiliation(s)
- Saurabh Singhal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 500 W. Thomas Road, Suite 500, Phoenix, AZ, USA
- Clinical and Translational Sciences, Creighton University, 2500 California Plaza, Omaha, NE, USA
| | - Harit Kapoor
- Clinical and Translational Sciences, Creighton University, 2500 California Plaza, Omaha, NE, USA
| | - Saravanan Subramanian
- Clinical and Translational Sciences, Creighton University, 2500 California Plaza, Omaha, NE, USA
| | - Devendra K Agrawal
- Clinical and Translational Sciences, Creighton University, 2500 California Plaza, Omaha, NE, USA
| | - Sumeet K Mittal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 500 W. Thomas Road, Suite 500, Phoenix, AZ, USA.
- Clinical and Translational Sciences, Creighton University, 2500 California Plaza, Omaha, NE, USA.
| |
Collapse
|
|
11
|
Lu C, Yu Y, Li L, Yu C, Xu P. Systematic review of the relationship of Helicobacter pylori infection with geographical latitude, average annual temperature and average daily sunshine. BMC Gastroenterol 2018; 18:50. [PMID: 29665777 PMCID: PMC5905136 DOI: 10.1186/s12876-018-0779-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 04/11/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection is a worldwide threat to human health with high prevalence. In this study, we analyzed the relationship between latitude, average annual temperature, average daily sunshine time and H. pylori infection. METHODS The PubMed, ClinicalTrials.gov , EBSCO and Web of Science databases were searched to identify studies reporting H. pylori infection. Latitude 30° was the cut-off level for low and mid-latitude areas. We obtained information for latitude, average annual temperature, average daily sunshine, and Human Development Index (HDI) from reports of studies of the relationships with H. pylori infection. RESULTS Of the 51 studies included, there was significant difference in H. pylori infection between the low- and mid-latitude areas (P = 0.05). There was no significant difference in the prevalence of H. pylori infection in each 15°-latitude zone analyzed (P = 0.061). Subgroup analysis revealed the highest and lowest H. pylori infection rates in the developing regions at > 30° latitude subgroup and the developed regions at < 30° latitude subgroup, respectively (P < 0.001). Multivariate analysis showed that average annual temperature, average daily sunshine time and HDI were significantly correlated with H. pylori infection (P = 0.009, P < 0.001, P < 0.001), while there was no correlation between H. pylori infection and latitude. CONCLUSIONS Our analysis showed that higher average annual temperature was associated with lower H. pylori infection rates, while average daily sunshine time correlated positively with H. pylori infection. HDI was also found to be a significant factor, with higher HDI associated with lower infection rates. These findings provide evidence that can be used to devise strategies for the prevention and control of H. pylori.
Collapse
Affiliation(s)
- Chao Lu
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003 China
| | - Ye Yu
- Department of Rheumatology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 China
| | - Lan Li
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003 China
| | - Chaohui Yu
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003 China
| | - Ping Xu
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003 China
| |
Collapse
|
|
12
|
Rouphael C, Kamal A, Sanaka MR, Thota PN. Vitamin D in esophageal cancer: Is there a role for chemoprevention? World J Gastrointest Oncol 2018; 10:23-30. [PMID: 29375745 PMCID: PMC5767790 DOI: 10.4251/wjgo.v10.i1.23] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 11/10/2017] [Accepted: 12/06/2017] [Indexed: 02/05/2023] Open
Abstract
Vitamin D has emerged as a promising anti-cancer agent due to its diverse biological effects on tumor differentiation, apoptosis and suppression of cellular proliferation. Current evidence suggests a protective role of vitamin D in colon cancer. The effect of vitamin D on esophageal cancer remains controversial. Multiple studies investigated the association between vitamin D and esophageal cancer, employing different modes of assessment of vitamin D status such as serum 25-hydroxyvitamin D levels, vitamin D dietary intake or exposure to ultraviolet B (UVB) radiation. Genetic variations of the vitamin D receptor (VDR) gene and VDR expression in esophageal specimens have also been investigated. Ecological studies evaluating exposure to UVB radiation yielded an inverse correlation with esophageal cancer. When vitamin D dietary intake was assessed, direct association with esophageal cancer was observed. However, circulating 25-hydroxyvitamin D concentrations showed inconsistent results. In this review article, we present a detailed summary of the current data on the effects of vitamin D on various histological subtypes of esophageal cancer and their precursor lesions. Well-powered prospective studies with accurate measurement of vitamin D status are needed before chemoprevention with vitamin D is recommended, as current evidence does not support a chemopreventive role of vitamin D against esophageal cancer. Future studies looking at the incidence of esophageal cancer in patients with pre-cancerous lesions (Barrett's esophagus and squamous cell dysplasia) receiving vitamin D supplementation are needed.
Collapse
Affiliation(s)
- Carol Rouphael
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Afrin Kamal
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Madhusudhan R Sanaka
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Prashanthi N Thota
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, United States
| |
Collapse
|
|
13
|
Cummings LC, Thota PN, Willis JE, Chen Y, Cooper GS, Furey N, Bednarchik B, Alashkar BM, Dumot J, Faulx AL, Fink SP, Kresak AM, Abusneineh B, Barnholtz-Sloan J, Leahy P, Veigl ML, Chak A, Markowitz SD. A nonrandomized trial of vitamin D supplementation for Barrett's esophagus. PLoS One 2017; 12:e0184928. [PMID: 28922414 PMCID: PMC5602627 DOI: 10.1371/journal.pone.0184928] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023] Open
Abstract
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.
Collapse
Affiliation(s)
- Linda C. Cummings
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
- Medical Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America
- * E-mail:
| | - Prashanthi N. Thota
- Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Joseph E. Willis
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Yanwen Chen
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
| | - Gregory S. Cooper
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
| | - Nancy Furey
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
| | - Beth Bednarchik
- William T. Dahms Clinical Research Unit, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
| | - Bronia M. Alashkar
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - John Dumot
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Ashley L. Faulx
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Medical Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America
| | - Stephen P. Fink
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
| | - Adam M. Kresak
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Basel Abusneineh
- Medical Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America
| | | | - Patrick Leahy
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
- Division of General Medical Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Martina L. Veigl
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
- Division of General Medical Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Amitabh Chak
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
| | - Sanford D. Markowitz
- Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America
| |
Collapse
|
|
14
|
Pang C, LaLonde A, Godfrey TE, Que J, Sun J, Wu TT, Zhou Z. Bile salt receptor TGR5 is highly expressed in esophageal adenocarcinoma and precancerous lesions with significantly worse overall survival and gender differences. Clin Exp Gastroenterol 2017; 10:29-37. [PMID: 28223834 PMCID: PMC5304980 DOI: 10.2147/ceg.s117842] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Bile acid reflux in the esophagus plays an important role in the carcinogenesis of esophageal adenocarcinoma (EAC). The G-protein coupled bile acid receptor (TGR5) has been associated with the development of gastrointestinal cancer. However, little is known regarding the role of TGR5 in esophageal carcinoma and precancerous lesions. We analyzed genomic DNA from 116 EACs for copy number aberrations via Affymetrix SNP6.0 microarrays. The TGR5 gene locus was amplified in 12.7% (14/116) of the EACs. The TGR5 protein expression was also assessed using immunohistochemistry from tissue microarrays, including Barrett’s esophagus (BE), low-(LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CM), squamous epithelium (SE), EAC and squamous cell carcinoma. The TGR5 protein was highly expressed in 71% of EAC (75/106), 100% of HGD (11/11), 72% of LGD (13/18), 66% of BE (23/35), 84% of CM (52/62), and 36% of SE (30/83). The patients with high expression of TGR5 exhibited significantly worse overall survival compared to the patients with nonhigh expression. TGR5 high expression was significantly increased in the males compared to the females in all cases with an odds ratio of 1.9 times. The vitamin D receptor (VDR) was significantly correlated with TGR5 expression. Our findings indicated that TGR5 may play an important role in the development and prognosis of EAC through a bile acid ligand. Gender differences in TGR5 and VDR expression may explain why males have a higher incidence of EAC compared to females.
Collapse
Affiliation(s)
- Chunhong Pang
- Department of Pathology, China-Japan Friendship Hospital; Department of Pathology and Laboratory Medicine
| | - Amy LaLonde
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY
| | - Tony E Godfrey
- Department of Surgery, Boston University Medical Center, Boston, MA
| | - Jianwen Que
- Center for Human Development; Division of Digestive and Liver Diseases, Columbia University, New York, NY
| | - Jun Sun
- Division of Gastroenterology and Hepatology, University of Illinois College of Medicine, Chicago, IL, USA
| | - Tong Tong Wu
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY
| | | |
Collapse
|
|
15
|
Zgaga L, O'Sullivan F, Cantwell MM, Murray LJ, Thota PN, Coleman HG. Markers of Vitamin D Exposure and Esophageal Cancer Risk: A Systematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev 2016; 25:877-86. [PMID: 27030602 DOI: 10.1158/1055-9965.epi-15-1162] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 03/20/2016] [Indexed: 12/11/2022] Open
Abstract
Vitamin D has been associated with reduced risk of many cancers, but evidence for esophageal cancer is mixed. To clarify the role of vitamin D, we performed a systematic review and meta-analysis to evaluate the association of vitamin D exposures and esophageal neoplasia, including adenocarcinoma, squamous cell carcinoma (SCC), Barrett's esophagus, and squamous dysplasia. Ovid MEDLINE, EMBASE, and Web of Science were searched from inception to September 2015. Fifteen publications in relation to circulating 25-hydroxyvitamin D [25(OH)D; n = 3], vitamin D intake (n = 4), UVB exposure (n = 1), and genetic factors (n = 7) were retrieved. Higher [25(OH)D] was associated with increased risk of cancer [adenocarcinoma or SCC, OR = 1.39; 95% confidence interval (CI), 1.04-1.74], with the majority of participants coming from China. No association was observed between vitamin D intake and risk of cancer overall (OR, 1.03; 0.65-1.42); however, a nonsignificantly increased risk for adenocarcinoma (OR, 1.45; 0.65-2.24) and nonsignificantly decreased risk for SCC (OR, 0.80; 0.48-1.12) were observed. One study reported a decreased risk of adenocarcinoma with higher UVB exposure. A decreased risk was found for VDR haplotype rs2238135(G)/rs1989969(T) carriers (OR, 0.45; 0.00-0.91), and a suggestive association was observed for rs2107301. In conclusion, no consistent associations were observed between vitamin D exposures and occurrence of esophageal lesions. Further adequately powered, well-designed studies are needed before conclusions can be made. Cancer Epidemiol Biomarkers Prev; 25(6); 877-86. ©2016 AACR.
Collapse
Affiliation(s)
- Lina Zgaga
- Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Republic of Ireland.
| | - Fiona O'Sullivan
- Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Republic of Ireland
| | - Marie M Cantwell
- Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Liam J Murray
- Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Prashanthi N Thota
- Center of Swallowing & Motility Disorders, Center of Excellence for Barrett's Esophagus, Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio
| | - Helen G Coleman
- Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland, United Kingdom
| |
Collapse
|
|
16
|
Wen Y, Da M, Zhang Y, Peng L, Yao J, Duan Y. Alterations in vitamin D signaling pathway in gastric cancer progression: a study of vitamin D receptor expression in human normal, premalignant, and malignant gastric tissue. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:13176-13184. [PMID: 26722516 PMCID: PMC4680461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 09/25/2015] [Indexed: 06/05/2023]
Abstract
Amount of studies in cells and animal models have proved vitamin D has multifarious antitumor effects. However, epidemiological studies showed inconsistent result on gastric cancer. The antitumor role is mainly mediated by the vitamin D receptor (VDR). Our hypothesis is that VDR may be abnormally (poorly) expressed in gastric cancer tissue. Present study is aimed at discovering and analyzing VDR expression in a series of human gastric tissues, including normal, premalignant, and malignant gastric tissue, and correlated VDR to the clinicopathological parameters of gastric cancer patients. VDR expression was detected by immunohistochemistry. The χ(2) test was used to analyze the VDR expression as well as the relationship between VDR and the clinicopathological factors of gastric cancer patients. Compared with normal (82.61%) and premalignant tissues (73.64%), VDR was lower expressed in cancer tissues (57.61%), with a statistically significant difference (P = 0.001). Among cancer tissues, VDR was higher expressed in well and moderate differentiated tissues contrasted with tissues with poor differentiation, and higher expressed in small tumors (< 5 cm) compared with large tumors (≥ 5 cm), with a statistically significant difference respectively (P = 0.016, P = 0.009). A decline linear trend appeared when analyzing the statistical difference of VDR expression among normal, premalignant, and malignant gastric tissues. VDR expression has been on the decline from the premalignant stage, finally low expressed in gastric cancer tissues, especial in poorly differentiated tissues. VDR could be a potential prognostic factor for patients with gastric cancer.
Collapse
Affiliation(s)
- Yanghui Wen
- Clinical Medical College of Ningxia Medical UniversityYinchuan 750004, P.R. China
| | - Mingxu Da
- Department of Surgical Oncology, Gansu Province People’s HospitalLanzhou 730000, P.R. China
| | - Yongbin Zhang
- Department of Surgical Oncology, Gansu Province People’s HospitalLanzhou 730000, P.R. China
| | - Lingzhi Peng
- Clinical Medical College of Ningxia Medical UniversityYinchuan 750004, P.R. China
| | - Jibin Yao
- Department of Surgical Oncology, Gansu Province People’s HospitalLanzhou 730000, P.R. China
| | - Yaoxing Duan
- Department of Surgical Oncology, Gansu Province People’s HospitalLanzhou 730000, P.R. China
| |
Collapse
|
|
17
|
Janmaat VT, Van De Winkel A, Peppelenbosch MP, Spaander MCW, Uitterlinden AG, Pourfarzad F, Tilanus HW, Rygiel AM, Moons LMG, Arp PP, Krishnadath KK, Kuipers EJ, Van Der Laan LJW. Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk. Mol Med 2015; 21:346-54. [PMID: 25910066 DOI: 10.2119/molmed.2012.00336] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 04/21/2015] [Indexed: 12/22/2022] Open
Abstract
Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5' regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention.
Collapse
Affiliation(s)
- Vincent T Janmaat
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Anouk Van De Winkel
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - André G Uitterlinden
- Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Farzin Pourfarzad
- Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Hugo W Tilanus
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Agnieszka M Rygiel
- Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - Leon M G Moons
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Pascal P Arp
- Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Kausilia K Krishnadath
- Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.,Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Luc J W Van Der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| |
Collapse
|
|
18
|
Hargrove L, Francis T, Francis H. Vitamin D and GI cancers: shedding some light on dark diseases. ANNALS OF TRANSLATIONAL MEDICINE 2014; 2:9. [PMID: 25332985 DOI: 10.3978/j.issn.2305-5839.2013.03.04] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 03/28/2013] [Indexed: 12/20/2022]
Abstract
VITAMIN D SYNTHESIS AND SIGNALING AFFECTS NUMEROUS CELLULAR PROCESSES INCLUDING: proliferation, differentiation and apoptosis. It is now commonly recognized that low levels of vitamin D are associated with a greater risk of tumorigenesis. Cancers of the gastrointestinal tract are most often difficult to diagnose and treat as patients typically present with progressed disease. Basic research, clinical trials and population studies have supported the concept that treatment with Vitamin D may be a therapeutic option when treating GI cancers, however treatments must be individualized and monitored closely as the side effects from Vitamin D treatment can be increasingly harmful. This review will highlight the most recent findings regarding Vitamin D signaling and GI cancers.
Collapse
Affiliation(s)
- Laura Hargrove
- 1 Scott & White Digestive Disease Research Center, 2 Division of Research, Central Texas Veterans Health Care System, 3 Department of Internal Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA
| | - Taylor Francis
- 1 Scott & White Digestive Disease Research Center, 2 Division of Research, Central Texas Veterans Health Care System, 3 Department of Internal Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA
| | - Heather Francis
- 1 Scott & White Digestive Disease Research Center, 2 Division of Research, Central Texas Veterans Health Care System, 3 Department of Internal Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA
| |
Collapse
|
|
19
|
Zhou Z, Xia Y, Bandla S, Zakharov V, Wu S, Peters J, Godfrey TE, Sun J. Vitamin D receptor is highly expressed in precancerous lesions and esophageal adenocarcinoma with significant sex difference. Hum Pathol 2014; 45:1744-51. [PMID: 24951052 DOI: 10.1016/j.humpath.2014.02.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 01/28/2014] [Accepted: 02/07/2014] [Indexed: 12/19/2022]
Abstract
Bile acid reflux into the esophagus is important in the development of esophageal adenocarcinoma (EAC). Recently, vitamin D receptor (VDR) was recognized as a bile acid receptor as well as a vitamin receptor. Expression of VDR is reported to influence the development of various types of cancer, such as those of the breast, liver, and colon. However, little is known about the role of VDR in esophageal neoplasms. We investigated the clinicopathological role of VDR in esophageal tumors. We analyzed genomic DNA from 116 EACs for copy number aberrations. The VDR locus was amplified in 7% of EACs. Expression of the VDR protein was also detected by immunohistochemistry from tissue microarrays created from tissues of Barrett esophagus (BE), low-grade (LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CCM), squamous epithelium (SE), EAC, and esophageal squamous cell carcinoma (ESCC). The protein was highly expressed in 88% of CCM (58/66), 95% of BE (35/37), 100% of the 19 LGD, 94% of HGD (15/16), and 79% of EAC (86/109), but expression in SE and ESCC was rare. Female patients with EAC and CCM were significantly less likely to have high VDR expression than male patients. The overall survival rate was significantly different for patients with tumors exhibiting VDR amplification versus nonamplification. Our findings suggest that VDR plays a role in the early development of EAC through a bile acid ligand. The sex difference in VDR expression may help to explain why men have a high incidence of EAC.
Collapse
Affiliation(s)
- Zhongren Zhou
- Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642.
| | - Yinglin Xia
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642
| | - Santhoshi Bandla
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642
| | - Vladislav Zakharov
- Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642
| | - Shaoping Wu
- Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612
| | - Jeffery Peters
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642
| | - Tony E Godfrey
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642
| | - Jun Sun
- Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612.
| |
Collapse
|
|
20
|
Trowbridge R, Kizer RT, Mittal SK, Agrawal DK. 1,25-dihydroxyvitamin D in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma. Expert Rev Clin Immunol 2014; 9:517-33. [PMID: 23730883 DOI: 10.1586/eci.13.38] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The incidence of reflux-related esophageal disease - Barrett's esophagus and esophageal adenocarcinoma - is rising, and the prognosis remains poor. Evidence exists that 1,25-dihydroxyvitamin D may augment the course of colon, breast and prostate cancer but little knowledge exists regarding its impact on disease of the esophagus. Important immune cells involved in reflux-related esophageal disease include CD4(+) T cells, macrophages and dendritic cells, and key signaling pathways include Wnt, Hedgehog, NFκ-B and IL-6-JAK-STAT. There is an inter-relationship between these entities and 1,25-dihydroxyvitamin D, which has been described in animal models and some human tissue. Despite this, there is an incomplete understanding of how the immune cell population and signaling pathways contribute to the course and prognosis of Barrett's esophagus and esophageal adenocarcinoma. More investigation with a focus on the clinical outcomes of patients with Barrett's esophagus and esophageal adenocarcinoma and the immune cell population and cell signaling activity in the diseased esophagus is necessary to determine the immunomodulatory role of 1,25-dihydroxyvitamin D in the pathogenesis of esophageal diseases.
Collapse
Affiliation(s)
- Ryan Trowbridge
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, USA
| | | | | | | |
Collapse
|
|
21
|
Trowbridge R, Mittal SK, Agrawal DK. Vitamin D and the epidemiology of upper gastrointestinal cancers: a critical analysis of the current evidence. Cancer Epidemiol Biomarkers Prev 2013; 22:1007-14. [PMID: 23563888 DOI: 10.1158/1055-9965.epi-13-0085] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Prospective analyses have yet to uncover a consistent relationship between vitamin D status and incidence and mortality of rarer cancers including esophageal and upper gastrointestinal cancers. We searched PubMed for literature about the epidemiology of upper gastrointestinal cancers and vitamin D published over the last decade and then summarized and critiqued the results of these studies in this review. The search yielded nine relevant studies. Overall, no consistent relationship was reported between serum vitamin D levels or a surrogate and upper gastrointestinal cancers. Four studies reported negative correlations between vitamin D status and upper gastrointestinal cancer, three reported positive correlations, one reported no correlation, and one reported both positive and negative correlations. No relationship has been established on the basis of epidemiologic data, but studies examining sun exposure consistently report an inverse association with esophageal cancer. The current literature is limited by the methods used to assess vitamin D status, lack of specific data for the types of upper gastrointestinal cancer, and failure to establish a temporal relationship between vitamin D status assessment and presentation of upper gastrointestinal cancer. It is possible that the lack of a consistent relationship is a consequence of inaccurate and imprecise assessment of vitamin D status.
Collapse
Affiliation(s)
- Ryan Trowbridge
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA
| | | | | |
Collapse
|