Background:
In human hepatocellular carcinoma (HCC), targeted treatment options are very limited, highlighting the fact that a huge translational gap exists between experimental studies and their clinical application. One important reason for this gap lies in the fact that mouse models of hepatocarcinogenesis strongly vary in their pathogenic routes and molecular profiles. Here, we took an innovative, systematic biological approach to overcome the translational limitation of single mouse HCC models and to identify previously unrecognized microRNA-dependent pathways in human HCC.
Methods:
We developed an algorithm for systematically integrating miRNA-expression profiles from 3 highly distinct, prototypic mouse HCC models (DEN: chemically-driven, tet-o-myc: oncogene-driven, LTa/b: inflammation-driven). Effects of candidate miRNAs on cell proliferation, apoptosis and invasion were analyzed in Huh7, Hep3B and JHH2 HCC cells. For target gene identification, we combined in-silico target gene prediction with mRNA arrays from all 3 mouse models. We translated our experimental findings into several cohorts of human HCC patients and tested correlations with patient survival times. Finally, the effects of miRNA mimics and mRNA knock down were examined in preclinical HCC models.
Results:
We identified one miRNA – miR-193a-5 p – that was commonly downregulated in all three tumor models and – in line with the underlying hypothesis – showed a concordant, previously unrecognized downregulation in human HCC. We could demonstrate that miR-193a-5 p regulates proliferation, survival, migration and invasion of liver tumor cells via the microtubule-associated protein NUSAP1. Low levels of miR-193a-5 p as well as increased levels of NUSAP1 in HCC samples correlated with shorter survival times of patients. Moreover, therapeutic targeting of miR-193 – 5 p or NUSAP1 in mice in either a xenograft HCC model or in an endogenous liver cancer model driven by hydrodynamic tail vein injection of cMyc-Akt1 plasmids yielded promising tumor responses.
Conclusion:
miR-193a-5 p inhibits HCC promotion by downregulating NUSAP1, a pathway that is highly conserved between mice and humans and therefore represents a promising therapeutic target in human HCC. Beyond the specific translational and therapeutic potential of these findings, our study provides a paradigm how innovative, system-biological approaches in mice can enrich the likelihood to identify pathways relevant in human liver disease.
