IKKα kinase inactivation induces pulmonary inflammation and spontaneous lung SCCs in mice.

  • Major finding: IKKα kinase inactivation induces pulmonary inflammation and spontaneous lung SCCs in mice.

  • Mechanism: IKKα reduction enhances expression of ΔNp63 and TRIM29 and promotes macrophage infiltration.

  • Impact: This mouse model recapitulates human lung SCC and identifies potential therapeutic targets.

Lung squamous cell carcinomas (SCC) are associated with smoking and are derived from keratin 5 (KRT5)–positive cells of the bronchial epithelium. Although dysregulation of several genes has been identified in human lung SCCs, mouse models that recapitulate these tumors are lacking. Loss of IκB kinase alpha (IKKα) has been implicated in the development of skin SCCs and has been reported in human lung SCCs, but the role of this kinase in lung tumorigenesis is unknown. Xiao and colleagues found that knockin mice expressing kinase-dead mutant IKKα developed spontaneous lung SCCs with increasing age as well as squamous cell hyperplasia and SCCs in other epithelial tissues. Kinase inactivation resulted in reduced IKKα expression in mutant lungs, and reintroduction of wild-type IKKα in KRT5-expressing cells suppressed lung epithelial cell proliferation and tumor formation, suggesting that IKKα downregulation promotes tumorigenesis. These tumors expressed lung SCC markers, including KRT5, p63, and tripartite motif-containing 29 (TRIM29); IKKα transcriptionally suppressed TRIM29 and the N-terminal truncated form of p63, ΔNp63, in both human and mouse lung epithelial cells via epigenetic regulation of histone modifications. In addition, murine lung SCCs shared many molecular alterations with human lung SCCs, including increased expression of stem cell regulators and oncogenes such as c-MYC and reduced levels of the tumor suppressors p53 and RB. IKKα reduction also triggered elevated expression of inflammatory cytokines and enhanced macrophage infiltration in mutant lungs, similar to findings in human lung SCC samples. Depletion of macrophages or reconstitution of IKKα-mutant mice with wild-type bone marrow prevented lung SCC formation, supporting a role for inflammatory signaling and macrophage-induced oxidative stress in lung SCC pathogenesis. These results establish a mouse model of lung SCC that can be used to identify and evaluate potential therapeutic targets.

Xiao Z, Jiang Q, Willette-Brown J, Xi S, Zhu F, Burkett S, et al. The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 2013;23:527–40.

©2013 American Association for Cancer Research.
2013