氡暴露、白细胞介素-6启动子变异与 former铀矿矿工的肺鳞状细胞癌

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

作者信息

Leng Shuguang, Thomas Cynthia L, Snider Amanda M, Picchi Maria A, Chen Wenshu, Willis Derall G, Carr Teara G, Krzeminski Jacek, Desai Dhimant, Shantu Amin, Lin Yong, Jacobson Marty R, Belinsky Steven A

机构信息

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

出版信息

Environ Health Perspect. 2016 Apr;124(4):445-51. doi: 10.1289/ehp.1409437. Epub 2015 Sep 15.

DOI:10.1289/ehp.1409437

PMID:26372664

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4829998/

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.

摘要

背景

高氡暴露是鳞状细胞癌的一个风险因素，鳞状细胞癌是在以前的铀矿工人中观察到的一种主要的肺癌组织学类型。氡暴露可引起氧化应激，导致肺部炎症。白细胞介素-6（IL-6）是一种促癌的炎性细胞因子，在肺癌发展中起关键作用。

目的

我们评估了IL6启动子中的单核苷酸多态性（SNP）是否与职业性高氡暴露的前铀矿工人的肺癌有关。

方法

在一项针对前铀矿工人的病例对照研究（242例病例和336例对照）中评估基因关联。使用来自肺癌与吸烟的基因环境关联研究（GENEVA）全基因组关联研究（GWAS）的数据进行重复研究。使用体外方法对SNP的功能相关性进行表征。

结果

我们发现rs1800797与矿工中的鳞状细胞癌相关，并且与病例中大量暴露期中点与诊断之间的较短时间相关。此外，rs1800797在GENEVA数据集中也与从不吸烟者的肺癌相关。功能研究表明，风险等位基因与基础IL-6 mRNA水平升高和更高的启动子活性相关。此外，具有风险等位基因的成纤维细胞在过氧化氢或苯并[a]芘二环氧物处理后显示出更大的IL-6分泌诱导。