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Requirement of NEMO/IKKγ for effective expansion of KRAS-induced precancerous lesions in the pancreas

Oncogene volume 32, pages 2690–2695 (2013)Cite this article

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Abstract

Pancreatic carcinoma, a leading cause of cancer death, is thought to develop out of pancreatic intraepithelial neoplasia (PanIN). PanIN lesions have not yet attained the fully malignant phenotype, but show increased proliferation and dysplasia, and frequently bear an oncogenic KRAS mutation. Pancreatic cancer development is associated with increased activity of the transcription factor NF-κB. NEMO (IKKγ) is a subunit of the IKK complex essential for the activation of canonical NF-κB signaling and has been ascribed both oncogenic and tumor-suppressive roles in gastrointestinal tumors. Here, we wanted to address the function of NEMO in pancreatic tumorigenesis. We therefore conditionally ablated NEMO in a mouse model for pancreatic carcinoma based on the expression of oncogenic KRAS in pancreatic precursor cells. Mice were analyzed for PanIN lesions and for the activation of associated signaling pathways. NEMO ablation in the pancreas, while in itself not causing any overt pathology, led to a drastic (>93%) decrease in the prevalence of both low-grade and high-grade PanIN in 10-month-old mice expressing oncogenic KRAS. Also, the inflammatory and fibrotic response associated with KRAS action in the pancreas was virtually abolished, including expression of inflammatory cytokines and activation of the interleukin-6/STAT3 axis. Moreover, the activation of MAPK signaling, Notch and KLF4 signaling normally observed in KRAS-induced PanIN was strongly reduced or absent when NEMO was ablated. Our study suggests that NEMO, an IKK subunit necessary for canonical NF-κB activation, is dispensable for normal pancreatic development and function, but essential for the propagation of KRAS-induced PanIN lesions.

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Acknowledgements

We thank Melanie Gerstenlauer, Ute Leschik, Uta Manfras and Ursula Möhnle for technical assistance, and Pedro Herrera and Marc Schmidt-Supprian for providing mice.

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Author notes

  1. T G Schips

    Present address: 4Current address: Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA,

Authors and Affiliations

  1. Institute of Physiological Chemistry, University of Ulm, Ulm, Germany

    H J Maier, T G Schips, H H Salem, B Baumann & T Wirth

  2. Department of Internal Medicine I, Center of Internal Medicine, University of Ulm, Ulm, Germany

    M Wagner

  3. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    H H Salem

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  1. H J Maier
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Correspondence to T Wirth.

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Maier, H., Wagner, M., Schips, T. et al. Requirement of NEMO/IKKγ for effective expansion of KRAS-induced precancerous lesions in the pancreas. Oncogene 32, 2690–2695 (2013). https://doi.org/10.1038/onc.2012.272

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  • DOI: https://doi.org/10.1038/onc.2012.272

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