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Xia X, Xu F, Dai D, Xiong A, Sun R, Ling Y, Qiu L, Wang R, Ding Y, Lin M, Li H, Xie Z. VDR is a potential prognostic biomarker and positively correlated with immune infiltration: a comprehensive pan-cancer analysis with experimental verification. Biosci Rep 2024; 44:BSR20231845. [PMID: 38639057 PMCID: PMC11065647 DOI: 10.1042/bsr20231845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/08/2024] [Accepted: 04/17/2024] [Indexed: 04/20/2024] Open
Abstract
The vitamin D receptor (VDR) is a transcription factor that mediates a variety of biological functions of 1,25-dihydroxyvitamin D3. Although there is growing evidence of cytological and animal studies supporting the suppressive role of VDR in cancers, the conclusion is still controversial in human cancers and no systematic pan-cancer analysis of VDR is available. We explored the relationships between VDR expression and prognosis, immune infiltration, tumor microenvironment, or gene set enrichment analysis (GSEA) in 33 types of human cancers based on multiple public databases and R software. Meanwhile, the expression and role of VDR were experimentally validated in papillary thyroid cancer (PTC). VDR expression decreased in 8 types and increased in 12 types of cancer compared with normal tissues. Increased expression of VDR was associated with either good or poor prognosis in 13 cancer types. VDR expression was positively correlated with the infiltration of cancer-associated fibroblasts, macrophages, or neutrophils in 20, 12, and 10 cancer types respectively and this correlation was experimentally validated in PTC. Increased VDR expression was associated with increased percentage of stromal or immune components in tumor microenvironment (TME) in 24 cancer types. VDR positively and negatively correlated genes were enriched in immune cell function and energy metabolism pathways, respectively, in the top 9 highly lethal tumors. Additionally, VDR expression was increased in PTC and inhibited cell proliferation and migration. In conclusion, VDR is a potential prognostic biomarker and positively correlated with immune infiltration as well as stromal or immune components in TME in multiple human cancers.
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MESH Headings
- Receptors, Calcitriol/genetics
- Receptors, Calcitriol/metabolism
- Humans
- Tumor Microenvironment/immunology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Prognosis
- Gene Expression Regulation, Neoplastic
- Thyroid Cancer, Papillary/immunology
- Thyroid Cancer, Papillary/genetics
- Thyroid Cancer, Papillary/pathology
- Thyroid Cancer, Papillary/metabolism
- Tumor-Associated Macrophages/immunology
- Tumor-Associated Macrophages/metabolism
- Thyroid Neoplasms/immunology
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/pathology
- Thyroid Neoplasms/metabolism
- Neoplasms/immunology
- Neoplasms/genetics
- Neoplasms/metabolism
- Neoplasms/pathology
- Cell Line, Tumor
- Cancer-Associated Fibroblasts/metabolism
- Cancer-Associated Fibroblasts/immunology
- Cancer-Associated Fibroblasts/pathology
- Databases, Genetic
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Affiliation(s)
- Xuedi Xia
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Feng Xu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Dexing Dai
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - An Xiong
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Ruoman Sun
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Yali Ling
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Lei Qiu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Rui Wang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Ya Ding
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Miaoying Lin
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Haibo Li
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Zhongjian Xie
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China
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He H, Zhang P, Li F, Zeng C, Liu D, Wu K. Predicting the prognosis of esophageal cancer based on extensive analysis of new inflammatory response‐related signature. J Biochem Mol Toxicol 2022; 37:e23291. [PMID: 36536508 DOI: 10.1002/jbt.23291] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/25/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022]
Abstract
The prognosis of esophageal cancer (ESCA) is very poor, with a 5-year survival rate of less than 20%. On the other hand, inflammation is the characteristic hallmark of ESCA; however, the prognostic relationship between inflammatory response-related genes and ESCA has not been clarified yet. Therefore, in the present manuscript, we intend to investigate the correlation and specific signature of inflammation for the prediction of the prognosis of ESCA. A total of 173 samples were obtained from The Cancer Genome Atlas (TCGA) database, including 162 tumors and 11 normal specimens. The prognostic signature was established by least absolute shrinkage and selection operator Cox regression analysis. The transcription factor regulatory network with genes of the prognostic signature was analyzed from the transcriptional regulatory relationships unravelled by sentence-based text-mining database. Chemotherapy sensitivity and immunotherapy analysis were also performed. Multivariate Cox analysis showed that the signature was an independent prognostic risk factor. The low-risk group had poorer outcomes than the high-risk group. In the high-risk group, the infiltration of most immune cells was high and strongly correlated with the riskScore. In chemotherapeutic drug sensitivity analysis, OSM, AHR, and BTG2 were significantly correlated with the current chemotherapeutic drugs of ESCA. We have demonstrated a valid prognostic signature of inflammatory response-related genes and found strong associations with immune cells, targeted genes, and chemotherapeutic agents.
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Affiliation(s)
- Hongbo He
- Department of Thoracic Surgery The First Affiliated Hospital of Zhengzhou University Henan Zhengzhou P. R. China
| | - Peng Zhang
- Department of Thoracic Surgery The First Affiliated Hospital of Zhengzhou University Henan Zhengzhou P. R. China
| | - Feng Li
- Department of Thoracic Surgery The First Affiliated Hospital of Zhengzhou University Henan Zhengzhou P. R. China
| | - Cheng Zeng
- Department of Thoracic Surgery The First Affiliated Hospital of Zhengzhou University Henan Zhengzhou P. R. China
| | - Donglei Liu
- Department of Thoracic Surgery The First Affiliated Hospital of Zhengzhou University Henan Zhengzhou P. R. China
| | - Kai Wu
- Department of Thoracic Surgery The First Affiliated Hospital of Zhengzhou University Henan Zhengzhou P. R. China
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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: 6] [Impact Index Per Article: 2.0] [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.
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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.)
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Peng Z, Liu XY, Cheng Z, Kai W, Song Z. Comprehensive analysis of a new immune-related prognostic signature for esophageal cancer and its correlation with infiltrating immune cells and target genes. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1576. [PMID: 34790782 PMCID: PMC8576727 DOI: 10.21037/atm-21-4756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 09/24/2021] [Indexed: 12/24/2022]
Abstract
Background The incidence of esophageal cancer (ESCA) is increasing rapidly, and the 5-year survival rate is less than 20%. This study provides new ideas for clinical treatment by establishing a prognostic signature composed of immune-related genes (IRGs), and fully analyzing its relationship with target genes and the tumor microenvironment (TME). Methods We downloaded the ESCA expression matrix and clinical information from The Cancer Genome Atlas (TCGA) database. Differential expression genes (DEGs) were identified with the edgeR package and crossed with the IRGs we obtained from the ImmPort database to obtain differential IRGs (DEIRGs). The prognostic signature was then obtained through univariate Cox, LASSO-Cox, and multivariate Cox analyses. The receiver operating characteristic (ROC) curve was used to evaluate the prediction effect of the model. The immune cell infiltration abundance obtained by ssGSEA and therapeutic target genes was used to perform sufficient correlation analysis with the obtained prognostic signature and related genes. Results A total of 173 samples were obtained from TCGA database, including 162 tumor and 11 normal samples. The 3,033 differential genes were used to obtain 254 DEIRGs by intersections with 2,483 IRGs (IRGs) obtained from the ImmPort Database. Finally, multivariate Cox regression analysis identified eight prognostic DEIRGs and established a new prognostic signature (HR: 2.49, 95% CI: 1.68–3.67; P<0.001). Based on the expression of the eight genes, the cohort was then divided into high and low risk groups and Kaplan-Meier (K-M) curves were plotted with the log-rank test P<0.0001 and 1-, 3-year area under the curve (AUC) >0.7. The K-M curves grouped according to high and low risks performed well in the two subgroup validation cohorts, with log-rank test P<0.05. There were differences in the degree of infiltration of 16 kinds of immune cells in tumor and normal samples, and the infiltration abundance of 12 kinds of immune cells was different in the high and low-risk groups. Conclusions An effective and validated prognostic signature composed of IRGs was established and had a strong correlation with immune cells and target genes of drug therapy.
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Affiliation(s)
- Zhang Peng
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin-Yuan Liu
- School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Zeng Cheng
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wu Kai
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhao Song
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Mahendra A, Karishma, Choudhury BK, Sharma T, Bansal N, Bansal R, Gupta S. Vitamin D and gastrointestinal cancer. J Lab Physicians 2020; 10:1-5. [PMID: 29403195 PMCID: PMC5784277 DOI: 10.4103/jlp.jlp_49_17] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vitamin D serves as a precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Low Vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus, and cancers. Metabolite of 1, 25-dihydroxyvitamin D3 (1,25[OH]2D3) regulates numerous genes that control gut physiology and homeostasis. 1,25(OH)2D3 serves various functions such as maintaining the integrity of epithelial barrier and absorption of calcium and phosphate, and the host's defense against pathogens, and the inflammatory response by several types of secretory and immune cells. Although epidemiological data remain inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for Vitamin D, results from some correlating studies strongly suggest that Vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding Vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome. The present review highlights the role of Vitamin D in cancer of the gastrointestinal tract including esophagus, gastric (stomach), liver, pancreas, and colon.
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Affiliation(s)
- Ashish Mahendra
- Department of Oral Pathology, Chandra Dental College, Barabanki, India
| | - Karishma
- Department Oral Medicine and Radiology, Sardar Patel Postgraduate Institute of Medical and Dental Sciences, Lucknow, Uttar Pradesh, India
| | - Basanta Kumar Choudhury
- Department Oral Medicine and Radiology, Institute of Dental Sciences and Sum Hospital, Kalinga Nagar, Shampur, Bhubaneswar, Odisha, India
| | - Tamanna Sharma
- Department of Oral Pathology, Himachal Dental College, Sundernagar, Mandi, Himachal Pradesh, India
| | - Neha Bansal
- Department Oral Medicine and Radiology, Dr HS Judge Institute of Dental Sciences, PU, Chandigarh, India
| | - Richa Bansal
- Department of Oral Pathology, Seema Dental College and Hospital, Rishikesh, Uttarakhand, India
| | - Shivangi Gupta
- Department of Periodontics and Implantology, Bhojia Dental College and Hospital, Nalagarh, Himachal Pradesh, India
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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.
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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
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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.
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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
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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.
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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.
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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.
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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
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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.
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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
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11
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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: 12] [Impact Index Per Article: 1.5] [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.
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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
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12
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Abdo J, Agrawal DK, Mittal SK. Basis for molecular diagnostics and immunotherapy for esophageal cancer. Expert Rev Anticancer Ther 2016; 17:33-45. [PMID: 27838937 DOI: 10.1080/14737140.2017.1260449] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Esophageal cancer (EC) is an extremely aggressive neoplasm, diagnosed in about 17,000 Americans every year with a mortality rate of more than 80% within five years and a median overall survival of just 13 months. For decades, the go-to regimen for esophageal cancer patients has been the use of taxane and platinum-based chemotherapy regimens, which has yielded the field's most dire survival statistics. Areas covered: Combination immunotherapy and a more robust molecular diagnostic platform for esophageal tumors could improve patient management strategies and potentially extend lives beyond the current survival figures. Analyzing a panel of biomarkers including those affiliated with taxane and platinum resistance (ERCC1 and TUBB3) as well as immunotherapy effectiveness (PD-L1) would provide oncologists more information on how to optimize first-line therapy for EC. Expert commentary: Of the 12 FDA-approved therapies in EC, zero target the genome. A majority of the approved drugs either target or are effected by proteomic expression. Therefore, a broader understanding of diagnostic biomarkers could give more clarity and direction in treating esophageal cancer in concert with a greater use of immunotherapy.
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Affiliation(s)
- Joe Abdo
- a Department of Clinical and Translational Science , Creighton University School of Medicine , Omaha , NE , USA
| | - Devendra K Agrawal
- a Department of Clinical and Translational Science , Creighton University School of Medicine , Omaha , NE , USA
| | - Sumeet K Mittal
- a Department of Clinical and Translational Science , Creighton University School of Medicine , Omaha , NE , USA.,b Department of Surgery , Creighton University School of Medicine (Phoenix campus), Norton Thoracic Institute, Dignity Health , Phoenix , AZ , USA
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13
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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; 25:877-886. [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.
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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
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14
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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.
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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
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15
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Huang GL, Yang L, Su M, Wang SK, Yin H, Wang JS, Sun GJ. Vitamin D3 and beta-carotene deficiency is associated with risk of esophageal squamous cell carcinoma - results of a case-control study in China. Asian Pac J Cancer Prev 2014; 15:819-23. [PMID: 24568502 DOI: 10.7314/apjcp.2014.15.2.819] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE The aim was to evaluate roles of vitamin D3 (VD3) and beta-carotene (BC) in the development of esophageal squamous cell carcinoma (ESCC) in a high-risk area, Huai'an District, Huai'an City, China. METHODS 100 new ESCC diagnosed cases from 2007 to 2008 and 200 residency- age-, and sex-matched healthy controls were recruited. Data were collected from questionnaires, including a food frequency questionnaire (FFQ) to calculate the BC intake, and reversed phase high-performance liquid chromatography (RP-HPLC) was used to measure the serum concentrations of BC and VD3. Odds ratios (OR) and 95% confidence intervals (CI) were calculated in conditional logistic regression models. RESULTS The average dietary intake of BC was 3322.9 μg (2032.4- 5734.3) in the case group and 3626.8 μg (1961.9-5827.9) in control group per capita per day with no significant difference by Wilcoxon test (p>0.05). However, the levels of VD3 and BC in the case group were significantly lower than in the control group (p<0.05). The OR values of the highest quartile and the lowest quartile of VD3 and BC in serum samples were both 0.13. CONCLUSION Our results add to the evidence that high circulating levels of VD3 and BC are associated with a reduced risk of ESCC in this Chinese population.
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Affiliation(s)
- Gui-Ling Huang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China E-mail :
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16
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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.
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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
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17
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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.
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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.
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18
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He D, Sun L, Li C, Hu N, Sheng Y, Chen Z, Li X, Chi B, Jin N. Anti-tumor effects of an oncolytic adenovirus expressing hemagglutinin-neuraminidase of Newcastle disease virus in vitro and in vivo. Viruses 2014; 6:856-74. [PMID: 24553109 PMCID: PMC3939485 DOI: 10.3390/v6020856] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 02/07/2014] [Accepted: 02/08/2014] [Indexed: 12/22/2022] Open
Abstract
Oncolytic virotherapy has been an attractive drug platform for targeted therapy of cancer over the past few years. Viral vectors can be used to target and lyse cancer cells, but achieving good efficacy and specificity with this treatment approach is a major challenge. Here, we assessed the ability of a novel dual-specific anti-tumor oncolytic adenovirus, expressing the hemagglutinin-neuraminidase (HN) gene from the Newcastle disease virus under the human telomerase reverse transcriptase (hTERT) promoter (Ad-hTERTp-E1a-HN), to inhibit esophageal cancer EC-109 cells in culture and to reduce tumor burden in xenografted BALB/c nude mice. In vitro, infection with Ad-hTERT-E1a-HN could inhibit the growth of EC-109 cells significantly and also protect normal human liver cell line L02 from growth suppression in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Ad-hTERT-E1a-HN also effectively and selectively decreased the sialic acid level on EC-109 cells, but not on L02 cells. Furthermore, Ad-hTERT-E1a-HN was shown to induce the apoptosis pathway via acridine orange and ethidium bromide staining (AO/EB staining), increase reactive oxygen species (ROS), reduce mitochondrial membrane potential and release cytochrome c. In vivo, xenografted BALB/c nude mice were treated via intratumoral or intravenous injections of Ad-hTERT-E1a-HN. Although both treatments showed an obvious suppression in tumor volume, only Ad-hTERT-E1a-HN delivered via intratumoral injection elicited a complete response to treatment. These results reinforced previous findings and highlighted the potential therapeutic application of Ad-hTERT-E1a-HN for treatment of esophageal cancer in clinical trials.
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Affiliation(s)
- Dongyun He
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Lili Sun
- Head and Neck Surgery, The Tumor hospital of Jilin province, Changchun 130001, China.
| | - Chang Li
- Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, China.
| | - Ningning Hu
- Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, China.
| | - Yuan Sheng
- Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, China.
| | - Zhifei Chen
- Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, China.
| | - Xiao Li
- Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, China.
| | - Baorong Chi
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Ningyi Jin
- Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, China.
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19
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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.
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Affiliation(s)
- Ryan Trowbridge
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, USA
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20
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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: 14] [Impact Index Per Article: 1.2] [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.
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Affiliation(s)
- Ryan Trowbridge
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA
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Xiong L, Cheng J, Gao J, Wang J, Liu X, Wang L. Vitamin D receptor genetic variants are associated with chemotherapy response and prognosis in patients with advanced non-small-cell lung cancer. Clin Lung Cancer 2013; 14:433-9. [PMID: 23522953 DOI: 10.1016/j.cllc.2013.01.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Revised: 01/21/2013] [Accepted: 01/29/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND The aim of this study was to explore the association between vitamin D receptor (VDR) genetic polymorphisms and platinum-based chemotherapy response as well as the prognosis of non-small-cell lung cancer (NSCLC) in a Chinese cohort. PATIENTS AND METHODS Seven hundred fifty-five patients with advanced NSCLC (stage III [A + B] or stage IV) were enrolled. Platinum-based chemotherapy was given to each patient with NSCLC, and the therapeutic effect was evaluated. The VDR polymorphisms were genotyped. RESULTS Three hundred twenty-one (42.5%) patients responded to chemotherapy (complete response [CR] or partial response [PR]) and 434 (57.5%) patients were nonresponders (stable disease [SD] or progressive disease [PD]). The genotypic and allelic frequencies of FokI, BsmI, and TaqI were not significantly different between chemotherapy responders and nonresponders. However, the genotypic and allelic frequencies of ApaI thymine (T) > guanine (G) were significantly different between the responders and nonresponders. Multivariate logistic regression analysis showed that GG genotype carriers of ApaI T > G had a higher chance of being responders. The ApaI T > G polymorphisms affected mean overall survival (OS). The GG genotype carriers of ApaI polymorphisms had a longer mean OS compared with TT carriers. Multivariate Cox regression analyses showed that ApaI T > G was significantly associated with OS. CONCLUSION We found that there was an effect of ApaI T > G polymorphisms of the VDR gene on the chemotherapy response in patients with NSCLC, as well as a prognostic role of the VDR gene polymorphisms in Chinese patients with advanced NSCLC.
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Affiliation(s)
- Liwen Xiong
- Department of Pulmonary Disease, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai 200030, P.R. China
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Trowbridge R, Mittal SK, Sharma P, Hunter WJ, Agrawal DK. Vitamin D receptor expression in the mucosal tissue at the gastroesophageal junction. Exp Mol Pathol 2012; 93:246-9. [PMID: 22664272 DOI: 10.1016/j.yexmp.2012.05.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 05/14/2012] [Indexed: 12/20/2022]
Abstract
Barrett's esophagus is considered to be a precursor to adenocarcinoma and the information on VDR expression in normal and Barrett's esophagus is significantly lacking. In this study, we examined the expression of VDR in the lower esophagus and gastric cardia of normal and Barrett's esophagus by immunofluorescence. Columnar mucosa but not squamous mucosa at the gastroesophageal junction showed positive immunofluorescence to VDR. Submucosal glands and ducts deep to the normal squamous mucosa stained positive for VDR and localized in the cytoplasm and perinuclear regions with no nuclear staining. Interestingly, Barrett's mucosa stained strongly positive for VDR. Glandular structures in the mucosal layer were far less abundant in the Barrett's mucosa than in the normal gastric mucosa. As a result, fewer structures deep to the Barrett's epithelial layer stained positive for VDR when compared to normal gastric mucosa. These findings suggest that in normal esophagus VDR expression is restricted to columnar epithelium and glandular structures. Furthermore, strong VDR expression in Barrett's mucosa may indicate an increased sensitivity of this tissue to endogenous or therapeutic effects of Vitamin D.
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Affiliation(s)
- Ryan Trowbridge
- Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA
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