Selenium, Cancer and Nutritional genomics from SNPs to molecular pathways Flashcards
What is cancer?
Multi-steps process; accumulation of genetic mutations leads to acquisition of tumour phenotype
What kinds of mutations can cause cancer?
Increase in cell survival or loss of cell death
Inhibition of repair mechanism, tumour suppressors or immune response
Decrease of genetic stability
Increase in angiogenesis
Increase in mobility
What is angiogenesis?
Formation of new blood cells
What are the main cancer prevention mechanisms?
Antioxidant mechanism
Tumour suppressor genes
Repair mechanism
Immunosurveillance
What is selenium?
AN anticarcinogenic trace element.
What kind of food is selenium rich?
Seafood
Nuts
Red meat
Eggs
What is the recommended uptake of Selenium for men per day in the UK?
75 micrograms
What is the recommended dose per day for women of selenium?
60 micrograms
Why is it important to maintain the optimal Selenium intake?
Required to support synthesis of selenoproteins
How many selenoproteins are there in humans?
25
What are the key roles of selenoproteins in cancer prevention mechanisms?
Anti-oxidant defences and redox signalling
Tumour suppression and control of survival
ER stress response
Immune system activation
How do selenoproteins support anti-oxidant defences and redox signalling?
Protect against oxidative damage in cytoplasm and mitochondria.
How do selenoproteins support ER stress response?
Proteins folding/removal of misfolded proteins.
Involved in ca2+ signalling.
What is the direct role of selenoproteins in tumour-suppression?
Act as tumour supressors
Activate other tumour suppressors
Which selenoproteins act as tumour supressors?
SELENOP
GPx3
Which tumour suppressors do selenoproteins activate?
p53
Which selenoproteins limit survival and proliferation of tumour cells?
GPx1
GPx4
SELENOP
SELENOF
What is the direct role of selenoproteins in immunosurveillance?
Activate the removal of the tumour cell by the immune system.
Which selenoproteins have a role in immunosurveillance?
SELENOP
TXNRD
Which selenoproteins act as antioxidant enzymes?
GPx
TNXRD
What is the geographical issue with selenoprotein?
Some areas have Se poor soil therefore that population will have lower Se intake.
What is the link between selenium intake and disease risk.
A very narrow risk-benefit window.
Too little, increases disease risk due to suboptimal intake.
Too much, increases disease risk, toxicity.
What happens when Se suboptimal?
Increased risk of cancer, type 2 diabetes, cardiovascular disease, dementia and risk of infection.
Why is the dose-response being a U shape difficult for treatment?
The optimal will be different for individuals.
What is the role of selenoproteins in the body?
Mediate Se biological actions using Se biological actors
How do selenoproteins contain Se?
In the form of the amino acid selenocysteine (Sec).
When is Sec incorporated into selenoproteins?
Sec incorporated in nascent
selenoprotein protein sequence during translation
What are the 2 main characteristics of selenoprotein charecteristics?
UGA codon, coding for Sec
SECIS stem loop RNA structure in 3’UTR
What does SECIS stand for?
SElenoCysteine Insertion Sequence
How does selenoprotein synthesis happen? (4 steps)
- Recruit tRNA(sec)
- Bind to SECIS
- Sec incorporated into selenoprotein
- Protein synthesis continues till STOP codon.
What does it mean that the selenoproteins have a hierarchy when Se levels are suboptimal?
Reduced Se means a reduced Sec bioavailability, sharing of Sec follows a hierarchy.
How are the selenoproteins low in the hierarchy stopped from being produced?
UGA codon signals ends on translation
Truncated proteins degraded
Which selenoproteins are high in the heirarchy?
GPx4
SEP15
Which selenoproteins are low on the hierarchy?
GPx1
SelS
What is the problem with Se supplementation trails?
Have conflicting results.
How do we advise people on Se supplementation?
Personal advice, due to the optimal varying in individuals.
Which selenoprotein functional SNPs were found to cause colorectal cancer in the czech cohort ?
SEPP1
SELS
GPX4
Which selenoprotein functional SNPs were found to cause to find breast cancer in the danish cohort?
SEPP1
GPX1
Which selenoprotein functional SNPs were found to cause to find prostate cancer in the german cohort?
SEPP1
GPX1
Which selenoprotein genes were found to cause to find prostate cancer in the German cohort through pathway analysis?
SELK
TXNRD1
TXNRD2
What does epidemiological data say about the role of SE in the protection against Prostate Cancer?
NPC trial decrease of prostate cancer when a low baseline Se levels.
SELECT trials prove supplementation has no effect on prostate cancer but increases the risk of type 2 diabetes in high Se status.
What is SEP15?
15kDa selenoprotein highly expressed in prostate tissue.
What gene codes for SEP15?
SELEOF gene
What is SEP15’s role?
Protein folding control in the ER and ER stress response.
Which SNP affects the activity of SEP15?
(A/G)
How does the SEP15 SNP affect who we can and cant supplement?
AA types have a higher mortality than benefit than GG/GA in high Se plasma status
Some benefit for GG/GA in high Se for prostate cancer risk
What is SePP?
60% of all plasma Se
Best biomarker of active Se
Where is Sepp synthesized?
Liver from dietary Se
What is the role of SePP?
Secreted in the plasma
Transports hepatic Se to other organs for synthesis of other selenoproteins.
What are the 2 plasma isoforms of SePP?
60kDa (10sec)
50kDa
Where are the 2 common SNPs in the SEPP1 gene?
In coding region
In the 3’UTR
What happened when SePP1 SNP individuals were supplemented with Se?
The effect of the SNPs disappears in Se supplemented volunteers.
What is Glutathione Peroxidase 4 (GPx4)?
Key enzyme in redox control and antioxidant defence in cytoplasm and mitochondria.
The rs713041 (C/T) in the GPX4 gene affects?
The sequence of GPX4 mRNA in 3’UTR, this is close to SECIS
The incorporation of Sec into GPX4 during translation
Position of GPX4 in the hierarchy
What do those carrying the C variant of the GPX4 gene have that those who have the T variant don’t?
Selenoprotein synthesis machine has a stronger affinity for SECIS in C.
C had a greater ability to promote Sec incorporation in GPX4
What does the presence of the T variant do for GPX4 in the selenoprotein hierarchy?
CC carriers are synthesised more than those of TT.
What is GPX1?
Oxidative stress response
Where are the functional SNPs for SEPP1?
Promoter
3’UTR
Coding SNP
Where are the functional SNPs for GPX4?
3’UTR
Where are the functional SNPs for SEP15?
3’UTR
Intron
Where are the functional SNPs for GPX1?
Coding SNP
What SNPs were found to have an effect on the risk of prostate cancer when genetic association was studied using the pathway analysis?
2 functional SNPs in SEPP1 and GPX1.
What tagSNPs were found to have an effect on the risk of prostate cancer when genetic association was studied using the pathway analysis?
SELK
TXNRD2
TXNRD1
What was the strategy for genetic association was studied using the pathway analysis in prostate cancer and selenoproteins?
384 tagSNP to capture genotype of all SNPs in 72 genes in whole Se metabolic pathway
Define GWAS?
Powerful approach to identify novel target/novel pathway influencing common diseased, but only explain a small fraction of the inherited risk.
What is the downfall of GWAs?
Some of the missing inherited risk can be attributed to gene X nutrient interactions.
What are the steps to studying the impact of nutrient on gene expression.
- Nutritional phenotyping
- Bioinformatics to compare experimental knowledge to database
What is NF-kB?
A transcription factor with a key role in inflammatory and immune response, cell survival and apoptosis.
Why is NF-KB important?
Impaired regulation leads to cancer development and progression.
How does NF-KB inhibition affect Selenoproteins?
Leads to the inability of individuals of suboptimal Se to respond to stress, pathogens and homeostasis.
