Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer
Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer
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DOI：
10.1096/fj.14-264580
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Chan Xiang;Jiucun Wang;X. Kou;Xiabin Chen;Zhaoyu Qin;Yan Jiang;Chang Sun;Ji-bin Xu;W. Tan
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文献类型：
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作者：
Chan Xiang;Jiucun Wang;X. Kou;Xiabin Chen;Zhaoyu Qin;Yan Jiang;Chang Sun;Ji-bin Xu;W. Tan
吸入的外源性物质，如烟草特异性致癌物4-（methylnitrosamino）-1-（3-吡啶基）-1-丁酮主要通过I相氧化酶细胞色素P450，家族2，亚家族A，多肽13（CYP 2A 13）、II相结合物UDP葡萄糖醛酸转移酶2家族，多肽B17（UGT 2B 17）和III相转运蛋白ATP结合盒，亚家族B（MDR/TAP），成员1（ABCB 1）代谢，与肺癌有关的基因多态性。它们的遗传相互作用和肺部表达调节在很大程度上尚不清楚。我们分析了2个独立肺癌病例群体（669名和566名患者）和1个常见对照群体（749名受试者）中CYP 2A 13和ABCB 1多态性的联合关联，并表征了肺发育相关转录因子叉头盒A2（FOXA 2）的处理功能。我们在肺上皮细胞系中进行了FOXA 2过表达和下调，分析了对CYP 2A 13、UGT 2B 17和ABCB 1反式激活的功能影响，并测量了它们在肺组织中表达的相关性。我们发现，与CYP 2A 13 R257 C基因型和ABCB 1顺式元件中由加塔结合蛋白6和FOXA 2协同靶向的功能调节变体的组合相关的癌症风险显著降低（OR 0.39; 95% CI 0.25 - 0.61; P相互作用= 0.029）。FOXA 2的遗传操作始终影响其与CYP 2A 13、UGT 2B 17和ABCB 1的启动子的结合和反式激活，这些启动子的mRNA和蛋白表达在肿瘤和正常肺组织中均与FOXA 2的mRNA和蛋白表达一致。因此，我们将FOXA 2确定为肺异生物质代谢途径的核心转录调节因子，并揭示了CYP 2A 13和ABCB 1之间的病因相关相互作用，进一步加深了我们对异生物质代谢系统表达和功能的理解。Xiang，C，Wang，J.，Kou，X.，陈旭，秦，Z.，江，Y.，孙角，澳-地徐，J，谭，W.，金，L.，林，D.，他，F.，Wang，H. CYP 2A 13和ABCB 1的肺表达受FOXA 2调节，它们的遗传相互作用与肺癌相关。FASEB J. 29，1986 - 1998（2015）。www.fasebj.org
Inhaled xenobiotics such as tobacco‐specific carcinogen 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone are mainly metabolized by phase I oxidase cytochrome P450, family 2, subfamily A, polypeptide 13 (CYP2A13), phase II conjugate UDP glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17), and phase III transporter ATP‐binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1), with genetic polymorphisms implicated in lung cancer. Their genetic interaction and pulmonary expression regulation are largely unknown. We analyzed joint association for CYP2A13 and ABCB1 polymorphisms in 2 independent lung cancer case populations (669 and 566 patients) and 1 common control population (749 subjects), and characterized the transacting function of the lung development‐related transcription factor forkhead box A2 (FOXA2). We undertook FOXA2 overexpression and down‐regulation in lung epithelial cell lines, analyzed functional impact on the trans‐activation of CYP2A13, UGT2B17, and ABCB1, and measured correlation for their expressions in lung tissues. We found a substantial reduction in cancer risk (OR 0.39; 95% CI 0.25‐0.61; Pinteraction = 0.029) associated with combined genotypes for CYP2A13 R257C and a functionary regulatory variant in the cis element of ABCB1 synergistically targeted by GATA binding protein 6 and FOXA2. Genetic manipulation of FOXA2 consistently influenced its binding to and transactivation of the promoters of CYP2A13, UGT2B17, and ABCB1, whose mRNA and protein expressions were all consistently correlated with those of FOXA2 in both tumorous and normal lung tissues. We therefore establish FOXA2 as a core transcriptional modulator for pulmonary xenobiotic metabolic pathways and uncover an etiologically relevant interaction between CYP2A13 and ABCB1, furthering our understanding of expression and function of the xenobiotic metabolism system.—Xiang, C, Wang, J., Kou, X., Chen, X., Qin, Z., Jiang, Y., Sun, C., Xu, J., Tan, W., Jin, L., Lin, D., He, F., Wang, H. Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer. FASEB J. 29, 1986‐1998 (2015). www.fasebj.org