title: The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas.
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. IKKα(low)K5(+)p63(hi) 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 IKKα(low)K5(+)p63(hi) 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.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Zuoxiang
authors.initials: Z
authors.lastname: Xiao
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.forename: Jami
authors.initials: J
authors.lastname: Willette-Brown
authors.forename: Sichuan
authors.initials: S
authors.lastname: Xi
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Sandra
authors.initials: S
authors.lastname: Burkett
authors.forename: Timothy
authors.initials: T
authors.lastname: Back
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Song
authors.forename: Mahesh
authors.initials: M
authors.lastname: Datla
authors.forename: Zhonghe
authors.initials: Z
authors.lastname: Sun
authors.forename: Romina
authors.initials: R
authors.lastname: Goldszmid
authors.forename: Fanching
authors.initials: F
authors.lastname: Lin
authors.forename: Travis
authors.initials: T
authors.lastname: Cohoon
authors.forename: Kristen
authors.initials: K
authors.lastname: Pike
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Yinling
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000096:biosynthesis; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D010750:Phosphoproteins; C550082:TRIM29 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D051550:I-kappa B Kinase