Mouse models of hepatocarcinogenesis: what can we learn for the prevention of human hepatocellular carcinoma?

Abstract

There is growing evidence that chronic inflammatory processes are involved in triggering the sequence from chronic liver injury to liver fibrosis, ultimately leading to liver cancer. In the last years this process has been recapitulated in a growing number of different mouse models. However, it has remained unclear whether and how these mouse models reflect the clinical reality of human hepatocellular carcinoma (HCC). Research with animal models but also human liver specimens has indicated that the NF-κB signaling pathway might withhold a crucial function in the mediation of chronic hepatic inflammation and the transition to HCC in humans. However, previous studies led to divergent and partly conflicting results with regards to the functional role of NF-κB in hepatocarcinogenesis. Here, we discuss a new genetic mouse model for HCC, the liver-specific TAK1 knockout mouse, which lacks the NF-κB activating kinase TAK1 specifically in parenchymal liver cells. Molecular findings in this mouse model and their possible significance for chemopreventive strategies against HCC are compared to other murine HCC models.

Figure 1:. Activation of canonical NF-κB signaling by TNF-α

Association of TNF-R1 results in TRADD-dependent TRAF2 and RIP1 recruitment. TRAF2 mediates K63-linked ubiquitination of RIP1 and recruits the IKK complex via the catalytic subunit NEMO. Autoubiquitination of TRAF2 causes TAK1 activation by interaction via TAB2/3. In cosequence TAK1 phosphorylate and activate IKKβ, which in turn phosphorylate IκBα, leading to his proteasomal degradation and releases NF-κB.

Figure 2:. (A) Representative macroscopic pictures of 7-9 weeks-old male WT (left panel), TAK1^LPC-KO (middle panel) and NEMO^LPC-KO livers (right panel)

Histological features of liver tumors in TAK1^LPC-KO and NEMOLPC-KO mice stained by H/E (lower panel, arrow head). TAK1^LPC-KO liver showed a clear cell HCC whereas NEMO^LPC-KO showed an eosinophilic, hepatoid HCC. (B) Serum level analysis of alanine aminotransferase (ALT), aspartate aminotransferase (AST). Results are shown as mean, error bars indicate SEM. **P<0.01, ***P<0.001 (n=5 each genotype).