Carcinogenesis Advance Access published online on August 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn190
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Published by Oxford University Press 2008.
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Constitutive Expression of Human Keratin 14 Gene in Mouse Lung Induces Premalignant Lesions and Squamous Differentiation
1 Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2 Laboratory of Animal Sciences, NCI-Frederick, Cancer Research, Frederick, MD, USA
* Correspondence: Ilona Linnoila, MD, Experimental Pathology Section, Cell and Cancer Biology Branch, CCR, NCI, NIH, 37 Convent Drive, Bldg37, Room 1056B, Bethesda, MD, 20892, USA, E-mail: linnoila{at}mail.nih.gov
Squamous cell carcinoma accounts for 20% of all human lung cancers, and is strongly linked to cigarette smoking. It develops through premalignant changes which are characterized by high levels of keratin 14 (K14) expression in the airway epithelium and evolve through basal cell hyperplasia, squamous metaplasia, and dysplasia to carcinoma in situ and invasive carcinoma. In order to explore the impact of K14 in the pulmonary epithelium that normally lacks both squamous differentiation and K14 expression, human K14 (hK14) gene was constitutively expressed in mouse airway progenitor cells using a mouse Clara cell specific 10kDa protein (CC10) promoter. While the lungs of CC10-hK14 transgenic mice developed normally, we detected increased expression of K14 and the molecular markers of squamous differentiation program such as involucrin, loricrin, small proline-rich protein 1A, transglutaminase 1 and cholesterol sulfotransferase 2B1. In contrast, wild type lungs were negative. Aging CC10-hK14 mice revealed multifocal airway cell hyperplasia, occasional squamous metaplasia and their lung tumors displayed evidence for multidirectional differentiation. We conclude that constitutive expression of hK14 initiates squamous differentiation program in the mouse lung, but fails to promote squamous maturation. Our study provides a novel model for assessing the mechanisms of premalignant lesions in vivo by modifying differentiation and proliferation of airway progenitor cells.
Key Words: Lung tumors • keratin 14 • squamous differentiation • transgenic mice • Clara cells
Received March 11, 2008; revised July 17, 2008; accepted August 7, 2008.
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