Role of IKKalpha in lung squamous cell carcinoma development. Lung cancer is the leading cause of cancer mortality worldwide;however, there are no robust animal models of lung squamous cell carcinomas (SCCs), one of the major types of lung cancer. We report that kinase-dead IKKalpha knock-in mice develop spontaneous lung SCCs associated with IKKalpha downregulation and marked pulmonary inflammation. IKKalpha reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKalphalowK5+p63hi cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKalpha, depleting macrophages, and reconstituting irradiated mutant animals with WT bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKalpha-mutant macrophages promote the transition of IKKalphalowK5+p63hi cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011391-03
Application #
8763487
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2013
Total Cost
$504,123
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Xiao, Zuoxiang; Jiang, Qun; Willette-Brown, Jami et al. (2013) The pivotal role of IKK* in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 23:527-40
Balkhi, Mumtaz Yaseen; Willette-Brown, Jami; Zhu, Feng et al. (2012) IKKýý-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis. Blood 119:5467-77