The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas

Zuoxiang Xiao, Qun Jiang, Jami Willette-Brown, Sichuan Xi, Feng Zhu, Sandra Burkett, Timothy Back, Na Young Song, Mahesh Datla, Zhonghe Sun, Romina Goldszmid, Fanching Lin, Travis Cohoon, Kristen Pike, Xiaolin Wu, David S. Schrump, Kwok Kin Wong, Howard A. Young, Giorgio Trinchieri, Robert H. WiltroutYinling Hu

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)527-540
Number of pages14
JournalCancer Cell
Volume23
Issue number4
DOIs
Publication statusPublished - 2013 Apr 15

Bibliographical note

Funding Information:
We thank Teri Plona, Scott Coccodrilli, Arati Raziuddin, Hue Vuong, Vika Grinberg, and Robin Stewart from Laboratory of Molecular Technology, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research for sequencing DDR2, Sox2, and PIK3CA genes in mouse lung SCCs and Dr. Hesed Padilla-Nash and Dr. Thomas Ried from National Institutes of Health for kindly providing a spontaneously transformed lung murine epithelial cell line M2C. This work was supported by the National Cancer Institute (ZIA BC 011212 and ZIA BC 011391 to Y.H.).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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