Asbestos-Induced Lung Cancer-Associated SNP rs13383928 Regulates PTH2R Expression in Lung Tissue.

IF 17.7 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2021-02-05 DOI:10.1159/000513291

Yuan-Qing Meng, Qiang Shi, Si-Jing Zhu, Guang-Huan He, Shi-Jiao Zhang, Chang Sun

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Abstract

Background: Lung cancer is one of the most common malignant tumors, and asbestos exposure was suggested to contribute to a proportion of lung cancer cases. Previous genome-wide gene-environment interaction analysis reported that rs13383928 was associated with asbestos-related lung cancer. However, the mechanism of this association was still unclear.

Methods: In the present study, we retrieved the genotype data from the 1,000 Genomes Project on single-nucleotide polymorphisms (SNPs) surrounding rs13383928 and analyzed the linkage disequilibrium (LD) pattern of this region. Further functional genomics analyses were performed.

Results: The result indicated that no other SNPs were in LD with rs13383928, suggesting that rs13383928 is the causal one. The following dual luciferase assay disclosed that the T allele of rs13383928 presented significantly higher enhancer activity than G in lung cells, thus verifying that this SNP was functional in the lung. Through chromosome conformation capture, the PTH2R (parathyroid hormone 2 receptor)promoter was identified to interact with the segment surrounding rs13383928. By chromatin immunoprecipitation, it was observed that the region spanning rs13383928 could bind transcription factor FOXJ2 (forkhead box J2).

Conclusion: Our functional genomics evidence supports a link between rs13383928 and asbestos-related lung cancer through regulating PTH2R.

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石棉诱发肺癌相关 SNP rs13383928 可调控肺组织中 PTH2R 的表达

背景：肺癌是最常见的恶性肿瘤之一：肺癌是最常见的恶性肿瘤之一，而石棉暴露被认为是导致部分肺癌病例的原因。之前的全基因组基因与环境相互作用分析表明，rs13383928 与石棉相关肺癌有关。然而，这种关联的机制尚不清楚：在本研究中，我们从千人基因组计划中检索了围绕 rs13383928 的单核苷酸多态性（SNPs）的基因型数据，并分析了该区域的连锁不平衡（LD）模式。此外，还进行了进一步的功能基因组学分析：结果表明，没有其他 SNP 与 rs13383928 存在 LD，这表明 rs13383928 是致病的 SNP。随后的双荧光素酶测定显示，rs13383928的T等位基因在肺细胞中的增强子活性明显高于G，从而验证了该SNP在肺中的功能。通过染色体构象捕获，确定了 PTH2R（甲状旁腺激素 2 受体）启动子与围绕 rs13383928 的区段相互作用。通过染色质免疫共沉淀法观察到，跨越rs13383928的区域可与转录因子FOXJ2（叉头盒J2）结合：我们的功能基因组学证据支持 rs13383928 通过调节 PTH2R 与石棉相关肺癌之间存在联系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.