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Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model

A Corrigendum to this article was published on 27 March 2015

This article has been updated

Abstract

Lung cancer is one of the leading cancer malignancies, with a five-year survival rate of only 15%. We have developed a lentiviral-vector-mediated mouse model, which enables generation of non-small-cell lung cancer from less than 100 alveolar epithelial cells, and investigated the role of IKK2 and NF-κB in lung-cancer development. IKK2 depletion in tumour cells significantly attenuated tumour proliferation and significantly prolonged mouse survival. We identified Timp1, one of the NF-κB target genes, as a key mediator for tumour growth. Activation of the Erk signalling pathway and cell proliferation requires Timp-1 and its receptor CD63. Knockdown of either Ikbkb or Timp1 by short hairpin RNAs reduced tumour growth in both xenograft and lentiviral models. Our results thus suggest the possible application of IKK2 and Timp-1 inhibitors in treating lung cancer.

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Figure 1: Lentiviral-vector-mediated mouse lung-cancer model.
Figure 2: IKK2 depletion in KrasG12D tumour cells prolonged mouse survival.
Figure 3: Timp1 expression induced by NF-κB activation in KrasG12D tumours.
Figure 4: IKK2 and Timp-1 are required to maintain high Erk activation.
Figure 5: Activation of FAK–Erk pathway and cell proliferation requires Timp-1 and CD63.
Figure 6: Knockdown of Ikbkb or Timp1 attenuated tumour growth.
Figure 7: Lung-cancer treatment using IKK2 inhibitor TPCA-1.

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  • 26 February 2015

    The version of this Article originally published should have acknowledged that this work was also supported by NIH grant number CA158191. This has been corrected in all online versions of the Article.

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Acknowledgements

We appreciate the generosity of M. Pasparakis for providing the IKK2fl/fl mouse, and T. Takeya and H. Nakajima for tissue-specific promoter plasmids. We thank L. Ouyang for assistance with microarray preparation. We also thank G. Pao, O. Singer, F. Liu, D. Morvinski, Q. Zhu and Y. Soda for advice on lentiviral vector designing and discussions, and G. Estepa for assistance with preparing frozen sections. N.Y. is supported by a fellowship from the Leona and Harry Helmsley Center for Nutritional Genomics (Salk Institute). I.M.V. is an American Cancer Society Professor of Molecular Biology, and holds the Irwin and Joan Jacobs Chair in Exemplary Life Science. This work was supported in part by grants from the National Institutes of Health, Leducq Foundation, Merieux Foundation, Ellison Medical Foundation, Ipsen/Biomeasure, Sanofi Aventis, Prostate Cancer Foundation, Department of Defense and the H.N. and Frances C. Berger Foundation. The project described was supported in part by grant number R37AI048034 from the National Institute of Allergy and Infectious Diseases, and Cancer Center Core Grant P30CA014195-38. This work was also supported by NIH grant number CA158191.

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Y.X. designed and carried out the experiments and wrote the paper. N.Y. carried out Timp-1-related experiments and microarray analysis. M.L. examined tumour samples and interpreted tumour histology. E.K. analysed the microarray data. Y.Z. and E.O. synthesized IKK2 inhibitors. R.J.S. provided mouse lines and gave advice on the project. I.M.V. supervised the project and wrote the paper.

Corresponding author

Correspondence to Inder M. Verma.

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The authors declare no competing financial interests.

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Xia, Y., Yeddula, N., Leblanc, M. et al. Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nat Cell Biol 14, 257–265 (2012). https://doi.org/10.1038/ncb2428

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