1. Wood dust exposure induces cell transformation through EGFR-mediated OGG1 inhibition.
- Author
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Staffolani S, Manzella N, Strafella E, Nocchi L, Bracci M, Ciarapica V, Amati M, Rubini C, Re M, Pugnaloni A, Pasquini E, Tarchini P, Valentino M, Tomasetti M, and Santarelli L
- Subjects
- Apoptosis, Blotting, Western, Bronchi metabolism, Cell Proliferation, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Cells, Cultured, DNA Glycosylases genetics, DNA Glycosylases metabolism, Epithelial Cells metabolism, ErbB Receptors genetics, Humans, Immunoenzyme Techniques, Neovascularization, Physiologic, Phosphorylation, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Bronchi pathology, Cell Transformation, Neoplastic pathology, DNA Glycosylases antagonists & inhibitors, Dust, Epithelial Cells pathology, ErbB Receptors metabolism, Occupational Exposure adverse effects, Wood chemistry
- Abstract
A high risk of neoplastic transformation of nasal and paranasal sinuses mucosa is related to the occupational exposure to wood dust. However, the role of occupational exposures in the aetiology of the airway cancers remains largely unknown. Here, an in vitro model was performed to investigate the carcinogenic effect of wood dusts. Human bronchial epithelial cells were incubated with hard and soft wood dusts and the DNA damage and response to DNA damage evaluated. Wood dust exposure induced accumulation of oxidised DNA bases, which was associated with a delay in DNA repair activity. By exposing cells to wood dust at a prolonged time, wood dust-initiated cells were obtained. Initiated-cells were able to form colonies in soft agar, and to induce blood vessel formation. These cells showed extensive autophagy, reduced DNA repair, which was associated with reduced OGG1 expression and oxidised DNA base accumulation. These events were found related to the activation of EGFR/AKT/mTOR pathway, through phosphorylation and subsequent inactivation of tuberin. The persistence in the tissue of wood dusts, their repetitious binding with EGFR may continually trigger the activation switch, leading to chronic down-regulation of genes involved in DNA repair, leading to cell transformation and proliferation., (© The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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