title: Epigenetic silencing of miR-218 by the lncRNA CCAT1, acting via BMI1, promotes an altered cell cycle transition in the malignant transformation of HBE cells induced by cigarette smoke extract.
abstract: Cigarette smoking is the strongest risk factor for the development of lung cancer, the leading cause of cancer-related deaths. However, the molecular mechanisms leading to lung cancer are largely unknown. A long-noncoding RNA (lncRNA), CCAT1, regarded as cancer-associated, has been investigated extensively. Moreover, the molecular mechanisms of lncRNAs in regulation of microRNAs (miRNAs) induced by cigarette smoke remain unclear. In the present investigation, cigarette smoke extract (CSE) caused an altered cell cycle and increased CCAT1 levels and decreased miR-218 levels in human bronchial epithelial (HBE) cells. Depletion of CCAT1 attenuated the CSE-induced decreases of miR-218 levels, suggesting that miR-218 is negatively regulated by CCAT1 in HBE cells exposed to CSE. The CSE-induced increases of BMI1 levels and blocked by CCAT1 siRNA were attenuated by an miR-218 inhibitor. Moreover, in CSE-transformed HBE cells, the CSE-induced cell cycle changes and elevated neoplastic capacity were reversed by CCAT1 siRNA or BMI1 siRNA. This epigenetic silencing of miR-218 by CCAT1 induces an altered cell cycle transition through BMI1 and provides a new mechanism for CSE-induced lung carcinogenesis.
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Luo
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Xinlu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Qianlei
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Junchao
authors.initials: J
authors.lastname: Xue
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
authors.forename: Le
authors.initials: L
authors.lastname: Shi
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China. Electronic address: drqzliu@hotmail.com.
authors.forename: Qizhan
authors.initials: Q
authors.lastname: Liu
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D045424:Complex Mixtures / Q000633:toxicity; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000187:drug effects; D063150:Polycomb Repressive Complex 1 / Q000096:biosynthesis* / Q000187:drug effects; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000187:drug effects; D034741:RNA, Small Interfering / Q000187:drug effects; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity; D014945:Wound Healing / Q000187:drug effects
chemical_list: C069077:BMI1 protein, human; C579842:CCAT1 long noncoding RNA, human; D045424:Complex Mixtures; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D063150:Polycomb Repressive Complex 1
keywords: Carcinogenesis; Cell cycle; Cigarette smoke extract (CSE); lncRNAs; miRNAs