Abstract

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.

Highlights

  • Liver carcinoma is one of the most common cancers and the second leading cause of cancer-related death worldwide [1]

  • The mice were analyzed for inflammation, fibrosis and tumor formation at different time points (Figure 1B)

  • IKK2ca expression resulted in activation of the NF-κB signaling pathway, as evidenced by the nuclear NF-κB DNA-binding activity in electrophoretic mobility shift assay (EMSA), p65 nuclear staining and western blot analysis (Figure 1E,F and Figures S1A,B and S7–S11)

Read more

Summary

Introduction

Liver carcinoma is one of the most common cancers and the second leading cause of cancer-related death worldwide [1]. About 80% of all liver cancers arise as a consequence of chronic liver disease. Chronic inflammation and the associated wound-healing response are strongly linked with the development of fibrosis, followed by cirrhosis, and hepatocellular carcinoma (HCC) [2]. About 80% of all HCCs are preceded by liver fibrosis and cirrhosis [3]. In general activation of NF-κB in parenchymal and non-parenchymal cells promotes inflammation, liver fibrosis, and hepatocarcinogenesis [14,15,16,17,18]. Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. We analyzed the consequences of inflammation and p53 loss in liver carcinogenesis

Methods
Results
Discussion
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.