title: Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mutation rates in cells maintaining episomal human papillomavirus 16 genomes.
abstract: High-risk human papillomavirus (HR-HPV) infections are necessary but insufficient agents of cervical and other epithelial cancers. Epidemiological studies support a causal, but ill-defined, relationship between tobacco smoking and cervical malignancies. In this study, we used mainstream tobacco smoke condensate (MSTS-C) treatments of cervical cell lines that maintain either episomal or integrated HPV16 or HPV31 genomes to model tobacco smoke exposure to the cervical epithelium of the smoker. MSTS-C exposure caused a dose-dependent increase in viral genome replication and correspondingly higher early gene transcription in cells with episomal HPV genomes. However, MSTS-C exposure in cells with integrated HR-HPV genomes had no effect on genome copy number or early gene transcription. In cells with episomal HPV genomes, the MSTS-C-induced increases in E6 oncogene transcription led to decreased p53 protein levels and activity. As expected from loss of p53 activity in tobacco-exposed cells, DNA strand breaks were significantly higher but apoptosis was minimal compared with cells containing integrated viral genomes. Furthermore, DNA mutation frequencies were higher in surviving cells with HPV episomes. These findings provide increased understanding of tobacco smoke exposure risk in HPV infection and indicate tobacco smoking acts more directly to alter HR-HPV oncogene expression in cells that maintain episomal viral genomes. This suggests a more prominent role for tobacco smoke in earlier stages of HPV-related cancer progression.
authors: Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, China, Department of Molecular Genetics and Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM 87131, USA and.
authors: Lanlan
authors: L
authors: Wei
authors: Department of Molecular Genetics and Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM 87131, USA and.
authors: Anastacia M
authors: AM
authors: Griego
authors: The First Affiliated Hospital of Harbin Medical University, Department of Neurosurgery, Harbin, Heilongjiang 150001, China.
authors: Ming
authors: M
authors: Chu
authors: Department of Molecular Genetics and Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM 87131, USA and mozbun@salud.unm.edu.
authors: Michelle A
authors: MA
authors: Ozbun
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000821:virology; D002584:Cervix Uteri / Q000187:drug effects* / Q000473:pathology / Q000821:virology*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000821:virology; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D052162:Human papillomavirus 16 / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D059645:Mutation Rate; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000235:genetics*; D010957:Plasmids; D012097:Repressor Proteins / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16