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- Title
Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer.
- Authors
Lee, K.-S.; Lee, Y.-S.; Lee, J.-M.; Ito, K.; Cinghu, S.; Kim, J.-H.; Jang, J.-W.; Li, Y.-H.; Goh, Y.-M.; Chi, X.-Z.; Wee, H.; Lee, H.-W.; Hosoya, A.; Chung, J.-H.; Jang, J.-J.; Kundu, J. K.; Surh, Y.-J.; Kim, W.-J.; Ito, Y.; Jung, H.-S.
- Abstract
Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3−/− mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3−/− bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3−/− epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/− mice (∼18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/− mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.
- Subjects
EPITHELIAL cells; LUNG aging; LUNG cancer; ADENOCARCINOMA; TUMORS; HYPERPLASIA
- Publication
Oncogene, 2010, Vol 29, Issue 23, p3349
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2010.79