Adipose tissue inflammation and  VDR  expression and methylation in colorectal cancer

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Abstract

Background

Lack of vitamin D (VD) has been associated with colorectal cancer (CRC). VD has anti-inflammatory effects and regulates several cellular pathways by means of its receptor, including epigenetic modifications. Adipose tissue dysfunction has been related to low-grade inflammation, which is related to diseases like cancer. The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D (25(OH)D), adipose tissue gene expression of VD receptor (VDR), pro-inflammatory markers, and the epigenetic factor DNA methyltransferase 3a (DNMT3A) as well as VDR promoter methylation in CRC.

Methods

Blood and visceral adipose tissue from 57 CRC and 50 healthy control subjects were collected. CRC subjects had lower serum 25(OH)D levels and higher VDR gene expression, and these were negatively correlated in the CRC group.

Results

Adipose tissue NFκB1, IL6, and IL1B gene expression were higher in the CRC subjects than in the control subjects. 25(OH)D correlated negatively with NFκB1 and CRP. In turn, CRP correlated positively with NFκB1, IL6, IL1B, and VDR gene expression as well as NFκB1 that correlated positively with IL6 and IL1B. DNMT3A mRNA was negatively correlated with serum 25(OH)D and positively correlated with VDR DNA methylation. VDR DNA methylation at position 4 had lower levels in the CRC group. Global NFκB1 methylation at dinucleotide 3 was lower in the CRC group.

Conclusion

Our results suggest that adipose tissue may be a key factor in CRC development. The low 25(OH)D levels and high adipose tissue VDR expression in CRC may, at least in part, mediate this relationship by modifying adipose tissue DNA methylation and promoting inflammation.

Electronic supplementary material

The online version of this article (10.1186/s13148-018-0493-0) contains supplementary material, which is available to authorized users.

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Most cited references 28

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Adipose tissue, adipokines, and inflammation.

Giamila Fantuzzi (2005)

White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-alpha, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.

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Prospective study of predictors of vitamin D status and cancer incidence and mortality in men.

Edward L. Giovannucci, Yan Liu, Eric Rimm … (2006)

Vitamin D has potent anticancer properties, especially against digestive-system cancers. Many human studies have used geographic residence as a marker of solar ultraviolet B and hence vitamin D exposure. Here, we considered multiple determinants of vitamin D exposure (dietary and supplementary vitamin D, skin pigmentation, adiposity, geographic residence, and leisure-time physical activity-to estimate sunlight exposure) in relation to cancer risk in the Health Professionals Follow-Up Study. Among 1095 men of this cohort, we quantified the relation of these six determinants to plasma 25-hydroxy-vitamin D [25(OH)D] level by use of a multiple linear regression model. We used results from the model to compute a predicted 25(OH)D level for each of 47,800 men in the cohort based on these characteristics. We then prospectively examined this variable in relation to cancer risk with multivariable Cox proportional hazards models. From 1986 through January 31, 2000, we documented 4286 incident cancers (excluding organ-confined prostate cancer and nonmelanoma skin cancer) and 2025 deaths from cancer. From multivariable models, an increment of 25 nmol/L in predicted 25(OH)D level was associated with a 17% reduction in total cancer incidence (multivariable relative risk [RR] = 0.83, 95% confidence interval [CI] = 0.74 to 0.92), a 29% reduction in total cancer mortality (RR = 0.71, 95% CI = 0.60 to 0.83), and a 45% reduction in digestive-system cancer mortality (RR = 0.55, 95% CI = 0.41 to 0.74). The absolute annual rate of total cancer was 758 per 100,000 men in the bottom decile of predicted 25(OH)D and 674 per 100,000 men for the top decile; these respective rates were 326 per 100,000 and 277 per 100,000 for total cancer mortality and 128 per 100,000 and 78 per 100,000 for digestive-system cancer mortality. Results were similar when we controlled further for body mass index or physical activity level. Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers. The vitamin D supplementation necessary to achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day.

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Architecture of the human regulatory network derived from ENCODE data.

Mark Gerstein, Anshul Kundaje, Manoj Hariharan … (2012)

Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.

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Author and article information

Contributors

Mercedes Clemente-Postigo: +34 951032648 , mer.cp@hotmail.com

Manuel Macias-Gonzalez: +34 951032648 , mmacias.manuel@gmail.com

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 25 April 2018

Publication date PMC-release: 25 April 2018

Publication date Collection: 2018

Volume: 10

Electronic Location Identifier: 60

Affiliations

[1 ]ISNI 0000 0001 2298 7828, GRID grid.10215.37, 1Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, , Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, ; Málaga, Spain

[2 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), ; Madrid, Spain

[3 ]ISNI 0000 0000 8816 6945, GRID grid.411048.8, Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), , Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela University (USC), ; Santiago de Compostela, Spain

[4 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), ; Madrid, Spain

[5 ]ISNI 0000 0000 9788 2492, GRID grid.411062.0, Unidad de Gestión Clínica de Oncología Intercentros Hospital Universitario Virgen de la Victoria, ; Málaga, Spain

Article

Publisher ID: 493

DOI: 10.1186/s13148-018-0493-0

PMC ID: 5921388

PubMed ID: 29719581

SO-VID: 96a9dcdb-0f92-4f86-86c7-664cf5c8e5f4

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 August 2017

Date accepted : 12 April 2018

Funding

Funded by: CIBER ISCIII

Award ID: CB06/03/0018

Funded by: ISCIII

Award ID: PI11/01661, PI15/0114

Funded by: Co-financed by the European Regional Development Fund

Award ID: FEDER

Funded by: FPU

Award ID: 13/04211

Funded by: Nicolas Monardes Programme from the “Servicio Andaluz de Salud, Junta de Andalucia

Award ID: C-0029-2014

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: vitamin d,vdr,dna methylation,low-grade inflammation,colorectal cancer,adipose tissue

Data availability:

ScienceOpen disciplines: Genetics

Keywords: vitamin d, vdr, dna methylation, low-grade inflammation, colorectal cancer, adipose tissue

Adipose tissue inflammation and VDR expression and methylation in colorectal cancer

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Karger: Oncology

Most cited references 28

Adipose tissue, adipokines, and inflammation.

Prospective study of predictors of vitamin D status and cancer incidence and mortality in men.

Architecture of the human regulatory network derived from ENCODE data.

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