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Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners.

Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA - Environ. Health Perspect. (2015)

Bottom Line: We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases.Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity.Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.

ABSTRACT

Background: High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development.

Objectives: We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas.

Methods: Genetic associations were assessed in a case-control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches.

Results: We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments.

Conclusions: An IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion.

Citation: Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445-451; http://dx.doi.org/10.1289/ehp.1409437.

No MeSH data available.


Related in: MedlinePlus

IL6 promoter activity by haplotype alleles. Luciferase reporter construct containing haplotype allele A-G-A8T12-C (Risk HAP) that carried variant alleles for rs1800797 (A) and rs1800795 (C) had significantly higher reporter activity than was observed for G-G-A10T11-G (Reference HAP) in HEK293 (p-value = 3.42 × 10–6), HFL1 (p-value = 1.86 × 10–5), and HBEC2 (p-value = 6.2 × 10–4). The height of the bar is the average luciferase activity standardized by the levels observed for G-G-A10T11-G set to one. The error bar is the standard deviation.
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f2: IL6 promoter activity by haplotype alleles. Luciferase reporter construct containing haplotype allele A-G-A8T12-C (Risk HAP) that carried variant alleles for rs1800797 (A) and rs1800795 (C) had significantly higher reporter activity than was observed for G-G-A10T11-G (Reference HAP) in HEK293 (p-value = 3.42 × 10–6), HFL1 (p-value = 1.86 × 10–5), and HBEC2 (p-value = 6.2 × 10–4). The height of the bar is the average luciferase activity standardized by the levels observed for G-G-A10T11-G set to one. The error bar is the standard deviation.

Mentions: IL6 promoter activity by haplotype alleles. The reporter assay showed that haplotype allele A-G-A8T12-C carrying the risk allele of rs1800797 had 45–92% increased promoter activity compared with G-G-A10T11-G in HFL1, HEK293, and HBEC2 cell lines (p-values < 0.00062; Figure 2).


Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners.

Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA - Environ. Health Perspect. (2015)

IL6 promoter activity by haplotype alleles. Luciferase reporter construct containing haplotype allele A-G-A8T12-C (Risk HAP) that carried variant alleles for rs1800797 (A) and rs1800795 (C) had significantly higher reporter activity than was observed for G-G-A10T11-G (Reference HAP) in HEK293 (p-value = 3.42 × 10–6), HFL1 (p-value = 1.86 × 10–5), and HBEC2 (p-value = 6.2 × 10–4). The height of the bar is the average luciferase activity standardized by the levels observed for G-G-A10T11-G set to one. The error bar is the standard deviation.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829998&req=5

f2: IL6 promoter activity by haplotype alleles. Luciferase reporter construct containing haplotype allele A-G-A8T12-C (Risk HAP) that carried variant alleles for rs1800797 (A) and rs1800795 (C) had significantly higher reporter activity than was observed for G-G-A10T11-G (Reference HAP) in HEK293 (p-value = 3.42 × 10–6), HFL1 (p-value = 1.86 × 10–5), and HBEC2 (p-value = 6.2 × 10–4). The height of the bar is the average luciferase activity standardized by the levels observed for G-G-A10T11-G set to one. The error bar is the standard deviation.
Mentions: IL6 promoter activity by haplotype alleles. The reporter assay showed that haplotype allele A-G-A8T12-C carrying the risk allele of rs1800797 had 45–92% increased promoter activity compared with G-G-A10T11-G in HFL1, HEK293, and HBEC2 cell lines (p-values < 0.00062; Figure 2).

Bottom Line: We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases.Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity.Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.

ABSTRACT

Background: High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development.

Objectives: We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas.

Methods: Genetic associations were assessed in a case-control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches.

Results: We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments.

Conclusions: An IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion.

Citation: Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445-451; http://dx.doi.org/10.1289/ehp.1409437.

No MeSH data available.


Related in: MedlinePlus