The Pivotal Role of IKKα in the Development of Spontaneous Lung Squamous Cell Carcinomas

• Published in: Cancer cell 2013-04, Vol.23 (4), p.527-540
• Main Authors: Xiao, Zuoxiang, Jiang, Qun, Willette-Brown, Jami, Xi, Sichuan, Zhu, Feng, Burkett, Sandra, Back, Timothy, Song, Na-Young, Datla, Mahesh, Sun, Zhonghe, Goldszmid, Romina, Lin, Fanching, Cohoon, Travis, Pike, Kristen, Wu, Xiaolin, Schrump, David S., Wong, Kwok-Kin, Young, Howard A., Trinchieri, Giorgio, Wiltrout, Robert H., Hu, Yinling
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Differentiation - physiology; Cell Growth Processes - physiology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; I-kappa B Kinase - physiology; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mice, Transgenic; Phosphoproteins - biosynthesis; Trans-Activators - biosynthesis; Transcription Factors - biosynthesis
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2013.03.009

Here, we report that kinase-dead IKKα knockin mice develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation. IKKα reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKαlowK5+p63hi cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKα, depleting macrophages, and reconstituting irradiated mutant animals with wild-type bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKα mutant macrophages promote the transition of IKKαlowK5+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. ► We establish a robust mouse lung SCC model that resembles human lung SCCs ► IKKα reduction deregulates oncogenes, tumor suppressors, and stem cell genes ► Increased IKKα mutant macrophages promote the initiation of lung SCCs ► IKKα prevents the abnormality of squamous cells in multiple epithelial organs