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. Wiltrout; Yinling Hu

doi:10.1016/j.ccr.2013.03.009

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

Department of Oral Biology

Research output: Contribution to journal › Article › peer-review

98 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. IKKα^lowK5⁺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^lowK5⁺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.

Original language	English
Pages (from-to)	527-540
Number of pages	14
Journal	Cancer Cell
Volume	23
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2013.03.009
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2013.03.009

Cite this

Xiao, Z., Jiang, Q., Willette-Brown, J., Xi, S., Zhu, F., Burkett, S., Back, T., Song, N. Y., Datla, M., Sun, Z., Goldszmid, R., Lin, F., Cohoon, T., Pike, K., Wu, X., Schrump, D. S., Wong, K. K., Young, H. A., Trinchieri, G., ... Hu, Y. (2013). The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas. Cancer Cell, 23(4), 527-540. https://doi.org/10.1016/j.ccr.2013.03.009

@article{ae84a426e639484393553b8301ceef66,

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. 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.",

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

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.). ",

year = "2013",

month = apr,

day = "15",

doi = "10.1016/j.ccr.2013.03.009",

language = "English",

volume = "23",

pages = "527--540",

journal = "Cancer Cell",

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Xiao, Z, Jiang, Q, Willette-Brown, J, Xi, S, Zhu, F, Burkett, S, Back, T, Song, NY, Datla, M, Sun, Z, Goldszmid, R, Lin, F, Cohoon, T, Pike, K, Wu, X, Schrump, DS, Wong, KK, Young, HA, Trinchieri, G, Wiltrout, RH & Hu, Y 2013, 'The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas', Cancer Cell, vol. 23, no. 4, pp. 527-540. https://doi.org/10.1016/j.ccr.2013.03.009

TY - JOUR

T1 - The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas

AU - Xiao, Zuoxiang

AU - Jiang, Qun

AU - Willette-Brown, Jami

AU - Xi, Sichuan

AU - Zhu, Feng

AU - Burkett, Sandra

AU - Back, Timothy

AU - Song, Na Young

AU - Datla, Mahesh

AU - Sun, Zhonghe

AU - Goldszmid, Romina

AU - Lin, Fanching

AU - Cohoon, Travis

AU - Pike, Kristen

AU - Wu, Xiaolin

AU - Schrump, David S.

AU - Wong, Kwok Kin

AU - Young, Howard A.

AU - Trinchieri, Giorgio

AU - Wiltrout, Robert H.

AU - Hu, Yinling

N1 - 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.).

PY - 2013/4/15

Y1 - 2013/4/15

N2 - 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.

AB - 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.

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ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

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