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Article

An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation

1
Department of Internal Medicine I, University Hospital Ulm, 89081 Ulm, Germany
2
Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital Ulm, 89081 Ulm, Germany
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Institute of Physiological Chemistry, Ulm University, 89081 Ulm, Germany
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Department of Visceral, Vascular and Endocrine Surgery, Halle University Hospital, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany
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Center for Translational Cancer Research (TranslaTUM), Technical University Munich, 81675 Munich, Germany
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Department of Internal Medicine II, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
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Institute of Pathology, Ruhr University Bochum, 44789 Bochum, Germany
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1410; https://doi.org/10.3390/cancers11101410
Received: 14 August 2019 / Revised: 13 September 2019 / Accepted: 18 September 2019 / Published: 21 September 2019
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
Background: Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver carcinogenesis. Methods: We used inducible liver-specific transgenic mouse strains to analyze the consequences of NF-κB/p65 activation mimicking chronic inflammation and subsequent p53 loss. Results: Ikk2ca driven NF-κB/p65 activation in mice results in liver fibrosis, the formation of ectopic lymphoid structures and carcinogenesis independent of p53 expression. Subsequent deletion of Trp53 led to an increased tumor formation, metastasis and a shift in tumor differentiation towards intrahepatic cholangiocarcinoma. In addition, loss of Trp53 in an inflammatory liver resulted in elevated chromosomal instability and indicated a distinct aberration pattern. Conclusions: In conclusion, activation of NF-κB/p65 mimicking chronic inflammation provokes the formation of liver carcinoma. Collateral disruption of Trp53 supports tumor progression and influences tumor differentiation and heterogeneity. View Full-Text
Keywords: inflammation; hepatocellular carcinoma; intrahepatic cholangiocarcinoma; ectopic lymphoid structures; progenitor cells inflammation; hepatocellular carcinoma; intrahepatic cholangiocarcinoma; ectopic lymphoid structures; progenitor cells
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MDPI and ACS Style

Svinarenko, M.; Katz, S.-F.; Tharehalli, U.; Mulaw, M.A.; Maier, H.J.; Sunami, Y.; Fischer, S.K.; Chen, Y.; Heurich, S.; Erkert, L.; Tannapfel, A.; Wirth, T.; Schirmbeck, R.; Seufferlein, T.; Lechel, A. An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation. Cancers 2019, 11, 1410. https://doi.org/10.3390/cancers11101410

AMA Style

Svinarenko M, Katz S-F, Tharehalli U, Mulaw MA, Maier HJ, Sunami Y, Fischer SK, Chen Y, Heurich S, Erkert L, Tannapfel A, Wirth T, Schirmbeck R, Seufferlein T, Lechel A. An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation. Cancers. 2019; 11(10):1410. https://doi.org/10.3390/cancers11101410

Chicago/Turabian Style

Svinarenko, Michael, Sarah-Fee Katz, Umesh Tharehalli, Medhanie A. Mulaw, Harald J. Maier, Yoshiaki Sunami, Sarah K. Fischer, Yuexin Chen, Sabine Heurich, Lena Erkert, Andrea Tannapfel, Thomas Wirth, Reinhold Schirmbeck, Thomas Seufferlein, and André Lechel. 2019. "An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation" Cancers 11, no. 10: 1410. https://doi.org/10.3390/cancers11101410

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