Selenium, Cancer, and Nutritional Genomics: From SNPs to Molecular Pathways
Selenium, Cancer and Nutritional Genomics
Carcinogenesis and Cancer Process
Carcinogenesis is a multi-step process where the accumulation of genetic mutations leads to the acquisition of a tumor phenotype. These mutations can:
Increase cell proliferation and survival, while inhibiting cell death.
Inhibit repair mechanisms, tumor suppressor genes, and immune response.
Increase genetic instability, leading to more mutations.
Increase angiogenesis to supply nutrients and oxygen to the tumor.
Increase mobility and metastatic properties, allowing the cancer to spread.
Cancer Prevention Mechanisms
Several mechanisms help prevent cancer:
Antioxidant mechanisms protect against oxidative stress.
Tumor suppressor genes prevent cell division; is an example.
Repair mechanisms include DNA repair and removal of misfolded proteins from the endoplasmic reticulum (ER) to combat ER stress.
Immunosurveillance involves the immune system identifying and removing cancerous cells.
Selenium: An Anticarcinogenic Trace Element
Selenium (Se) is a micronutrient essential for human health. It is found in Se-rich foods like seafood, Brazil nuts, liver, kidney, beef, meat, fish, eggs, and cereals.
Selenium plays roles in:
Cancer prevention mechanisms
Redox control
Thyroid function
Reproduction
Immune response
The recommended nutrient intake varies by age and sex. For example, in the UK, it's 75 μg/day for males and 60 μg/day for females, while in the US, it's 55 μg/day for both males and females.
Optimal Se intake is required to support selenoprotein synthesis. There are 25 selenoproteins in humans, which act as biological actors.
Selenoproteins and Anticancer Properties
Selenoproteins play vital roles in cancer prevention:
Antioxidant defenses & redox signaling: protect against oxidative damage in the cytoplasm and mitochondria via glutathione peroxidase (GPx) and thioredoxin reductases (TXNRD).
Tumor suppression: control proliferation and survival of tumor cells.
Endoplasmic reticulum stress response: aid in protein folding and removal of misfolded proteins, as well as Ca2+ signaling.
Immune system support: bolster immunosurveillance in cancer.
Selenoproteins and Cancer Prevention Pathways
Selenoproteins limit survival and proliferation of tumor cells, with GPx1, GPx4, SELENOP, and F playing crucial roles.
They contribute to tumor suppression by acting as tumor suppressors (SELENOP, GPx3) or activating other tumor suppressors like .
Selenoproteins participate in antioxidant and repair mechanisms through antioxidant enzymes (GPx, TNXRD) and ER stress response.
They also increase immunosurveillance, aiding in the removal of tumor cells via SELENOP and TXNRD.
GPx stands for glutathione peroxidases, and TXNRD stands for thioredoxin reductases. ER represents the endoplasmic reticulum.
Variations in Selenium Intake
There are significant differences in Se intake across different populations, largely due to geographic differences in soil Se content.
Very poor Se soil content (New Zealand, some regions of China) leads to Se deficiency.
Poor Se soil content (Europe, some regions of China, Africa, Middle-East, New Zealand) results in mostly low or sub-optimal intake.
Soil mostly rich in Se (most of the US, Canada/North America) leads to mostly adequate intake.
Some countries have opted for fertilizers containing Se (New Zealand, Finland).
Deficiency is rare, while sub-optimal intake is common. Optimal intake supports optimal selenoprotein synthesis. Supra-nutritional or toxic intake can lead to selenosis.
There's a narrow risk-benefit window for Se, where optimal intake is beneficial but excessive intake can be harmful.
Selenium Intake and Disease Risk
There is a U-shaped dose-response relationship between Se intake and human health:
Too little Se increases disease risk (deficiency is rare, but suboptimal intake is common).
Too much Se also increases disease risk (supra-nutritional intake and toxicity).
Optimal Se intake is required to optimize selenoprotein synthesis.
Suboptimal Se intake is associated with increased risk of cancer, type 2 diabetes (T2D), cardiovascular disease (CVD), dementia, and risk of infection. Individuals have different Se requirements depending on these factors.
Selenoproteins: Biological Actors
There are 25 selenoproteins in humans that mediate Se biological actions. They contain Se in the form of the amino acid selenocysteine (Sec).
Sec is incorporated into selenoproteins during translation. All 25 selenoproteins share Sec and the selenoprotein synthesis (translation) machinery.
mRNA Structure
mRNA structure includes 5' and 3' UTRs (untranslated regions) that regulate translation and mRNA stability. Key components include:
3 STOP potential codons: UAA, UAG, and UGA
Selenoprotein Synthesis
Selenocysteine (Sec) is synthesized from dietary Se, meaning selenoprotein synthesis depends on adequate Se intake.
Sec is incorporated into the nascent selenoprotein sequence during translation. Selenoprotein mRNAs have two key characteristics:
UGA codon: coding for Sec
SECIS: stem-loop RNA structure in the 3’UTR
In other mRNAs, UGA typically functions as a stop codon.
UGA Codon Recoding and Selenoprotein Synthesis Machinery
The UGA codon is recoded to Sec because proteins from the selenoprotein synthesis machinery:
Recruit tRNASec
Bind to SECIS
Incorporate Sec in selenoprotein
Protein synthesis continues until a STOP codon (UAA or UAG) is reached. All 25 selenoproteins share:
Selenoprotein synthesis machinery
Selenocysteine
If there is not enough Se in the diet, Sec becomes limiting, and selenoprotein synthesis is affected.
Selenoprotein Hierarchy
Low/suboptimal Se leads to reduced Sec bioavailability, and the sharing of Sec follows a hierarchy.
Selenoproteins high in the hierarchy have prioritized synthesis and are maintained.
Selenoproteins very low in the hierarchy are not synthesized.
When ribosomes reach UGA, which is recognized as a STOP codon, translation ends, and the truncated protein is degraded.
Selenoproteins low in the hierarchy experience reduced production during low/suboptimal Se intake.
Suboptimal Selenium and Selenoproteins
Low Sec from suboptimal Se leads to decreased selenoprotein synthesis and activity, which contributes to:
Increased damage and decreased repair
Cellular maintenance problems
Obesity
Cancers
Heart disease
Inflammation/immune dysfunction
Neurological disorders
Age-related disorders
Impaired response to pathogens
Diabetes
Specific selenoproteins affected include SEP15, GPX4, and SEPP1.
Effects of Selenium Supplementation
Several intervention trials have examined the effects of Se supplementation:
NPC (Nutritional Prevention of Cancer Trial): In individuals with low baseline Se, supplementation resulted in a ~50% reduction in prostate cancer (PCa) and colorectal cancer (CRC).
SELECT (Selenium & Vitamin E Cancer Prevention Trial): No effect on PCa was observed in individuals with high Se, but there was an increased risk of T2D.
PRECISE (Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms & Revascularization): High doses of Se led to increased mortality, while low doses led to decreased mortality.
NHANES III: Indicated a U-shaped response with the maximum reduction in mortality at a plasma Se level of ~135 µg/L.
These findings suggest conflicting outcomes with Se supplementation, and Se status is measured via plasma Se concentration.
Cancer and Selenium: Individual Differences
There are inter-individual differences in Se status and intake, with suboptimal Se being common in Europe and linked to increased cancer risk.
Intervention and observation studies suggest that Se supplementation:
Could be harmful (toxicity) and increase the risk for some cancers (e.g., bladder) or T2D in individuals with high/optimal intakes.
Could benefit individuals with suboptimal intake.
Recommendations involve providing personalized advice based on individual intake rather than population-level advice. Factors like genetic variations may also affect individual Se requirements.
Nutritional Genomics: Nutrigenetics and Nutrigenomics
Nutrigenetics focuses on:
Genomics: SNP, SNP x SNP, and SNP x nutrient interactions
Identifying genes/molecular pathways involved in disease mechanism/prevention
Understanding how diet's influence on health/disease balance depends on an individual's genetic makeup
Nutrigenomics focuses on:
Transcriptomics, proteomics, metabolomics, etc.
Impact of nutrients on gene/protein expression and, consequently, on molecular pathways
Selenium and Cancer: Impact on Cancer Pathways
Nutritional genomics examines the interplay between environmental and lifestyle factors like Se intake, as well as genetic factors (genetic variants in selenoprotein genes) to affect target molecular pathways involved in disease prevention mechanisms.
Genetic Variants in Selenoprotein Genes and Cancer Risk
Genetic variants (SNPs) in selenoprotein genes affect cancer risk in European populations.
SNPs in selenoprotein genes are linked to cancer risk.
SNP X Se and SNP x SNP interactions modulate disease risk, indicating that the genetic risk carried by these variants can be modified by Se intake and other SNPs in other selenoprotein genes.
Candidate SNP Approach
The candidate SNP approach focuses on functional SNPs in genes known to be involved in disease prevention mechanisms. This is a traditional approach and involves a limited number of SNPs.
Selenium and Prostate Cancer Risk
Epidemiological data suggests a role for Se in protection against prostate cancer (PCa), but supplementation trials have conflicting findings.
NPC Trial: Showed a 52% decrease in PCa incidence in the Se-supplemented group compared to placebo in individuals with low baseline Se.
SELECT: Showed no effect on PCa incidence but an increased risk of T2D in the Se/VitE supplemented group for individuals with already high Se status.
Prostate cancer risk and survival are affected by genotype for SNPs in the SELENOF (SEP15) gene.
SELENOF (SEP15) and Prostate Cancer
SEP15 is a 15kDa selenoprotein highly expressed in prostate tissue.
Plays a role in protein folding control (ER) and ER-stress response.
Genetic variant for SNP in SELENOF gene (rs561104, an intron region) is linked to PCa. Higher mortality risk was found in AA individuals compared with GA/GG genotypes.
Genetic Association Studies
Genetic association studies explain why we cannot supplement everyone with Se.
SEP15 is an ER-resident selenoprotein involved in quality control of protein folding.
SNP (A/G) in the intron region (rs561104) influences PCa mortality.
GG/GA genotypes benefit from increased plasma Se status.
SNP x Se: SNP interacts with plasma Se concentrations to modify PCa risk & mortality from PCa, reducing genetic risk carried by GG/GA genotypes.
Selenoprotein P (SePP, SEPP1, SELENOP)
SePP is the major plasma selenoprotein (60% plasma Se) and the best biomarker of active Se. It is synthesized in the liver from dietary Se and secreted in the plasma to transport hepatic Se to other organs for the synthesis of other selenoproteins.
There are two plasma isoforms: 60kDa (10sec) and 50kDa. Genetic variations exist in the SEPP1 gene, with two common SNPs:
In the coding region (rs3877899, Ala234Thr)
In the 3’UTR (rs7579, G/A)
Effects of SNPs in SEPP1 on SePP Isoforms and Se Bioavailability
Genotype for both SNPs in SEPP1 affects:
Pattern of SePP plasma isoforms
Synthesis of several blood selenoproteins
Se (Sec) bioavailability
The effect of these SNPs disappears in Se-supplemented volunteers. These SNPs also affect cancer risk in breast, colorectal, and prostate cancers.
GPx4 and Redox Control
hGlutathione Peroxidase 4 (GPx4) protein is a key enzyme in redox control and antioxidant defense in the cytoplasm and mitochondria.
rs713041 (C/T) in the GPX4 gene affects the sequence of GPx4 mRNA in the 3’UTR (close to SECIS) and Sec incorporation in GPx4 protein during translation.
The C allele has a greater ability to promote Sec incorporation in GPx4 during translation than T allele.
Human studies show that the synthesis of GPx4 is higher in CC carriers than TT carriers at low plasma Se status (no difference after Se supplementation).
Functional SNPs in Selenoprotein Genes
Functional SNPs identified in
SEPP1: Se transporter gene
GPX4: oxidative stress response, redox control
SEP15: ER stress, protein folding, Ca2+ signalling
GPX1: oxidative stress response
Concept: SNP x Se interaction, i.e., the combined influence of low Se intake and SNPs affecting Se bioavailability or selenoprotein synthesis/activity, could affect an individual’s capacity to respond to stress and thus, disease risk.
SNP x Se Interactions and Selenoprotein Hierarchy
Low Se status combined with a risk allele decreases Sec bioavailability, while high Se status negates the effect of the genotype.
SNPXSe & SNPxSNP interactions affect selenoprotein hierarchy, leading to redistribution of Sec and selenoprotein synthesis machinery.
Genetic Variants in Selenoprotein Genes and Colorectal Cancer Risk
Genetic variants in three selenoprotein genes (SELENOS, GPx4, SePP) increase CRC risk in a Czech cohort.
SePP supplies Sec.
GPx4 is involved in mitochondrial function, antioxidant activity, and redox control. The T variant decreases Sec incorporation in GPx4, GPx4 protein synthesis, and GPx4 in the selenoprotein hierarchy.
SELS plays a role in ER stress. A SNP affects SELENOS synthesis.
SNP x SNP x Se Interactions and Colorectal Cancer Risk
Individuals with combined genotypes for:
SNP in SEPP1 (GA variant: ↓ Sec availability)
SNP in GPX4 or SEP15 (↓ Sec inc.)
and low Se intake will have a reduced capacity to:
produce GPx4 (redox control, antioxidant defenses)
produce SeP15 (protein folding, ER stress)
respond to additional stress in low Se supply conditions. This could favor the switch towards cancer.
SNP x SNP x Se interactions further modulate CRC risk and reflect biological interactions of proteins in the same molecular pathway.
Pathway Analysis
Pathway analysis identifies genes (SNPs) within a molecular pathway suspected to be important in disease mechanisms. This serves as an indicator of the role of the molecular pathway in disease (prevention) mechanisms.
Multiple SNPs and Disease Risk
Cancer is a polygenic trait influenced by:
Multiple genetic variants (each with small individual effects)
Other factors (diet, smoking)
SNP x SNP interactions
SNP X E interactions
SNPs across the Se molecular pathway help identify candidate genes involved in traits.
Strategy for Identifying Novel SNPs in the Selenium Pathway
Identify all SNPs in the Se molecular pathway, which involves 72 genes related to stress response and cellular maintenance, including ER stress, protein folding, Ca2+ signaling, immune function, antioxidant activity, redox control, and mitochondrial function.
SNPs affecting selenoprotein synthesis or function could decrease an individual’s capacity to respond to stress and maintain cellular homeostasis.
Epidemiology: SNPs in the Selenium Molecular Pathway and Prostate Cancer
Low Se increases Prostate cancer (PCa) risk. Candidate SNPs, including two functional SNPs in SEPP1 & GPX1, affect PCa risk. Interactions between SNP and Se status modify PCa risk & progression.
GWAS and Gene-Nutrient Interactions
GWAS (Genome-Wide Association Studies) serve as a powerful approach to identify novel targets/pathways influencing common diseases, though they only explain a small fraction of the inherited risk.
Some of the missing inherited risk can be attributed to gene X nutrient interactions.
Summary 1: SNPs in Selenoprotein Genes and Their Consequences
Several functional SNPs in selenoprotein genes affect cancer risk (& other diseases).
Interaction SEP15 SNP (intron) X Se status influences survival to PCa.
2 SNPs in SEPP1 affect Se bioavailability, selenoprotein synthesis, PCa, and CRC risks.
SNP in GPX4 influences Sec incorporation and binding of selenoprotein synthesis machinery.
Consequences of Selenium X SNP or SNP x SNP interactions include effects on metabolic pathways implicated in individual’s response to stress, etc… and therefore can modulate disease risk.
Nutrigenetics approaches help us understand the influence of genetic variation on nutrition by investigating how gene expression or single-nucleotide polymorphisms affect a nutrient’s absorption, metabolism, elimination, and/or biological effects.
Selenium and Gene Expression: The Nutrigenomics Approach
Selenium levels affect gene expression in molecular pathways involved in cancer, immune/inflammatory function, and cytoskeleton remodeling.
Studying the Impact of Nutrients on Gene Expression: Multi-Omics Integration
The influence of nutrients on gene expression is investigated using a combination of 'omics' approaches:
Genomics: Analysis of genetic variants (SNP), mutations, DNA methylation pattern, and GxE interactions.
Transcriptomics: Measures RNA levels (transcriptome).
Proteomics: Studies protein expression and post-translational modifications (proteome).
Metabolomics: Examines the distribution of metabolites (metabolome) and enzymes.
Differences are assessed in genes (mutations, SNPs, methylation), RNA levels, proteins (levels + modifications), and enzymes + metabolites.
Experimental and Bioinformatics Approaches to Study Gene Expression
Study the impact of nutrient on gene expression through experimental data and bioinformatics approaches.
Step 1: Nutritional phenotyping using genomics, transcriptomics, proteomics, and metabolomics to gather experimental data.
Step 2: Bioinformatics comparisons of experimental data with knowledge databases (literature, gene & protein expression databases, mutations, SNPs databases) to identify lists of molecular pathways and key regulators.
Transcriptomics and Proteomics: Study Design
In a study involving 22 healthy volunteers, rectal biopsies were taken from two groups: suboptimal vs. optimal Se status, matched for sex, age, BMI. The study design involved:
Transcriptomics: Searching for genes differentially expressed between suboptimal and optimal plasma Se status.
Proteomics: Searching for proteins differentially expressed between suboptimal and optimal plasma Se status.
Results of Transcriptomics and Proteomics Analysis
Findings included: 254 genes differentially expressed, 69 genes with expression correlated to Se status, and 26 proteins differentially expressed.
Functional categories:
Cancer (80%)
Immune function & inflammatory responses (40%)
Cell growth & proliferation (70%)
Cellular movement & cell death (50%)
Individuals with sub-optimal Se status show decreased inflammatory & immune response capacity, impaired NFκB signaling, and cytoskeletal remodelling.
Key Molecular Players: NF-κB and Cytoskeletal Proteins
NF-κB (Nuclear factor-κB): A transcription factor with key roles in inflammatory and immune responses, cell survival and apoptosis, and cell proliferation. Aberrant regulation can contribute to cancer development and resistance to therapies.
Cytoskeletal proteins: Help with cell shape and movement. Deregulation is implicated in metastasis and tumor development.
Selenium's Influence on Immune Response and Tissue Integrity
Optimal Se: Supports recruitment of immune cells (T cells, B cells, Dendritic cells, Macrophages), promotes cell survival/apoptosis balance, maintains microbiota, and ensures healthy tissue and epithelial barrier function.
Sub-Optimal Se: Can result in reduced immunity, intermediate filaments remodeling, bacterial invasion due to altered epithelial barrier, chronic inflammation, tissue dysplasia, and altered cellular movement and morphology.
Summary 2: Nutrigenomics and Selenium's Impact on Molecular Pathways
Nutrigenomics approaches can be used to assess how nutrient status affects gene expression and metabolic pathways.
Selenium: reduction of immune and inflammatory responses and inhibiting NF-κB signaling in individuals with suboptimal intake can reduce their capacity to maintain homeostasis.
Alterations of the cytoskeleton in individuals with suboptimal Se intake could disrupt the epithelial barrier function in the colorectum.
The convergence of reduced immunity and inflammatory response together with cytoskeleton remodelling, can explain increased CRC in individuals with suboptimal Se status.
Integrating Nutrigenetics and Nutrigenomics for Personalized Nutrition
An integrated approach considers:
Nutrient intake/status
Genetic variants (risk/protective alleles)
Impact on molecular pathways (biomarkers)
to better understand individual dietary requirements and disease mechanisms for disease prevention.
Conclusions
Combined evidence from mechanistic, epidemiological, genetic association, and nutritional genomics studies suggests that suboptimal Se increases the risk of cancer by affecting cancer molecular pathways.
Se requirements and response to Se may be influenced by genetic variations in selenoprotein genes.
Nutritional genomics approaches can be used to identify novel candidate genes and pathways affected by a nutrient and involved in disease, and to identify potential novel early biomarkers for cancer.