title: Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer.
abstract: 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 trans-acting 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 transactivation 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.
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Chan
authors: C
authors: Xiang
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Jiucun
authors: J
authors: Wang
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Xiaochen
authors: X
authors: Kou
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Xiabin
authors: X
authors: Chen
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Zhaoyu
authors: Z
authors: Qin
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Yan
authors: Y
authors: Jiang
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Chang
authors: C
authors: Sun
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Jibin
authors: J
authors: Xu
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Wen
authors: W
authors: Tan
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Li
authors: L
authors: Jin
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Dongxin
authors: D
authors: Lin
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Fuchu
authors: F
authors: He
authors: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiothoracic Surgery, Changzheng Hospital of the Second Military Medical University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China haijianwang@fudan.edu.cn.
authors: Haijian
authors: H
authors: Wang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C496502:FOXA2 protein, human; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D051542:Hepatocyte Nuclear Factor 3-beta; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human
keywords: association study; gene expression regulation; polymorphism; respiratory toxicology; xenobiotic metabolizing enzyme