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82 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 83
FEBRUARY 13 - 16, 2014

THE FUNCTION OF FOS AND FOS~JUN DIMERS NOTES
IN LIVER CANCER

Rainer Hamacher , Osvaldo Graña , Latifa Bakiri , Erwin F. Wagner 1
1
2
1
1 Genes, Development and Disease Group, F-BBVA - CNIO Cancer Cell Biology
Programme, Structural Biology and Biocomputing Programme, Bioinformatics Unit,
2
Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Corresponding author’s e-mail: rwhamacher@cnio.es

Introduction: Hepatocellular carcinomas (HCC) are tumours associated with chronic
inflammation. The crosstalk between hepatocytes and non-parenchymal liver cells (NPCs)
is well established and involves important signalling molecules like MAPKs, NF-κB, AP-1,
Myc and STAT3. The proto-oncogene c-Jun, a component of the dimeric AP-1 transcription
BASIC SPEAKERS ABSTRACTS expression of the anti-apoptotic protein Survivin (Min et al., Nat Cell Biol, 2012). The c-Jun BASIC SPEAKERS ABSTRACTS
factor, is required for mouse liver tumourigenesis (Eferl et al., Cell, 2003). Moreover, c-Jun
promotes cell survival during tumour initiation by controlling c-Fos/SIRT6-dependent
partner c-Fos is frequently over-expressed in HCC, however, the in vivo function of c-Fos
in liver cancer remains to be defined.

Methodology: The chemical carcinogenesis (DEN) protocol was applied to genetically
engineered mouse models (GEMMs). We generated mice carrying novel tetracycline (tet)-
switchable hepatocyte-specific c-fos and forced jun~fos alleles (gain-of-function). We also
analyzed mice with conditional hepatocyte-specific deletion (loss-of-function) using Alfp-
Cre and conditional deletion of c-fos in hepatocytes and NPCs using Mx-Cre.
Results: Hepatocyte-specific ectopic expression of c-Fos in adult mice led to spontaneous
hyperproliferative dysplasia and promoted DEN-induced liver carcinogenesis. Interestingly,
when c-Fos dimerization was restricted to a single Jun partner, the resulting c-Jun~c-
Fos and JunD~c-Fos expressing mice displayed as well hyperproliferative dysplasia,
unlike JunB~c-Fos expressing mice. Deletion of c-Fos in hepatocytes protects from DEN-
induced liver carcinogenesis. Interestingly, deletion of c-Fos in NPCs and hepatocytes
abrogates this protective effect. Using whole transcriptome sequencing (RNA-Seq) the
steroid biosynthesis pathway was identified as being altered in a Fos- and cell-type-
dependent manner.

Conclusions: These results emphasize the cell-type-specific and dimer-dependent role
of c-Fos/AP-1 in liver disease. c-Fos is oncogenic in hepatocytes through dimerization
with c-Jun or JunD but not JunB, whereas c-Fos acts as a tumour suppressor in NPCs.
Mechanistically, c-Fos seems to inhibit the biosynthesis of steroids in a cell-type-specific
manner. Defining how c-Fos controls development of liver tumours and influences the
tumour microenvironment will help to identify new prognostic biomarkers and therapeutical
targets.