title: Cell cycle changes mediated by the p53/miR-34c axis are involved in the malignant transformation of human bronchial epithelial cells by benzo[a]pyrene.
abstract: Characterization of aberrant microRNA (miRNA) expression during carcinogen-induced cell transformation will lead to a better understanding of the role of miRNAs in cancer development. In this investigation, we evaluated changes in p53 function and its downstream target miRNAs in benzo[a]pyrene (BaP)-induced transformation of human bronchial epithelial (HBE) cells. Chronic exposure to BaP induced malignant transformation of cells, in which there were increased levels of mutant p53 (mt-p53) and reduced expression of wild-type p53 (wt-p53) and phosphorylated p53 (p-p53). With acute (12h) exposure to BaP, p-p53 was increased, and with increasing time of exposure (24h), the increase in p-p53 at a concentration of 1μM BaP was followed by a decline with increasing concentrations; wt-p53 and mt-p53 did not change. With prolonged exposure (48h), p-p53 and wt-p53 decreased, but mt-p53 increased. At different exposure times, the levels of miR-34c were consistent with p-p53. Over-expression of miR-34c resulted in inhibition of the BaP-induced G1-to-S transition and diminished up-regulation of cyclin D. Further, up-regulation of miR-34c or silencing of cylin D prevented BaP-induced malignant transformation. Thus, changes in the cell cycle mediated by the p53/miR-34c axis are involved in the transformation cells induced by BaP.
authors.affiliation: The First Clinic Medical College, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Zhuyu
authors.initials: Z
authors.lastname: Han
authors.affiliation: Jiangsu Center for Disease Control and Prevention, Nanjing 210029, Jiangsu, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The First Clinic Medical College, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ji
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Xu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Luo
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Bairu
authors.initials: B
authors.lastname: Wang
authors.affiliation: Jiangsu Center for Disease Control and Prevention, Nanjing 210029, Jiangsu, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Bian
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China. Electronic address: drqzliu@hotmail.com.
authors.forename: Qizhan
authors.initials: Q
authors.lastname: Liu
mesh_terms: D001564:Benzo(a)pyrene / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C530104:CCND1 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D001564:Benzo(a)pyrene
keywords: Benzo[a]pyrene (BaP); Cell cycle; Malignant transformation; miR-34c; p53