SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer
| العنوان: | SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer |
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| المؤلفون: | Gerard I. Evan, Doris M Rassl, Frank McCaughan, Peter McErlean, Emma L. Rawlins, Julien Bauer, Tariq Sethi, Hassan Farah, Paul Lavender, Trevor D. Littlewood, Jo-Anne Johnson, Lucia L. Correia, Robert C. Rintoul |
| المصدر: | American Journal of Respiratory and Critical Care Medicine. 195:1494-1508 |
| بيانات النشر: | American Thoracic Society, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung Neoplasms, business.industry, SOXB1 Transcription Factors, Early lung cancer, Cell Culture Techniques, Original Articles, Critical Care and Intensive Care Medicine, medicine.disease, Models, Biological, Surgery, 03 medical and health sciences, 030104 developmental biology, Research centre, Family medicine, Cancer centre, Carcinoma, Squamous Cell, Humans, Medicine, Bronchial dysplasia, business, Lung cancer, Bronchopulmonary Dysplasia |
| الوصف: | Improving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown that amplification of sex-determining region Y-box 2 (SOX2) is an early and consistent event in the pathogenesis of this disease, but its functional oncogenic potential remains uncertain. We tested the impact of deregulated SOX2 expression in a novel organotypic system that recreates the molecular and microenvironmental context in which squamous carcinogenesis occurs.(1) To develop an in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease; (2) to test the hypothesis that SOX2 deregulation is a key early event in the pathogenesis of bronchial dysplasia; and (3) to use the model for studies on pathogenesis and chemoprevention.We engineered the inducible activation of oncogenes in immortalized bronchial epithelial cells. We used three-dimensional tissue culture to build an organotypic model of bronchial dysplasia.We recapitulated human bronchial dysplasia in vitro. SOX2 deregulation drives dysplasia, and loss of tumor promoter 53 is a cooperating genetic event that potentiates the dysplastic phenotype. Deregulated SOX2 alters critical genes implicated in hallmarks of cancer progression. Targeted inhibition of AKT prevents the initiation of the dysplastic phenotype.In the appropriate genetic and microenvironmental context, acute deregulation of SOX2 drives bronchial dysplasia. This confirms its oncogenic potential in human cells and affords novel insights into the impact of SOX2 deregulation. This model can be used to test therapeutic agents aimed at chemoprevention. |
| تدمد: | 1535-4970 1073-449X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::41ee3b191ba097072ada734ebc8db72eTest https://doi.org/10.1164/rccm.201510-2084ocTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....41ee3b191ba097072ada734ebc8db72e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15354970 1073449X |
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