Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related
death. HCC incidence is on the rise, while treatment options remain
limited. Thus, a better understanding of the molecular pathways involved
in HCC development has become a priority to guide future therapies.
While previous studies implicated the AP-1 (Fos/Jun) transcription
factor family members c-Fos and c-Jun in HCC formation, the contribution
of Fos-related antigens 1 and 2 (Fra-1/2) is unknown. Here we show that
hepatocyte-restricted expression of a single chain
c-Jun~Fra-2 protein, which functionally mimics the
c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in
c-Jun~Fra-2hep mice. Several hallmarks
of human HCC, such as cell cycle dysregulation and the expression of HCC
markers are observed in liver tumors arising in
c-Jun~Fra-2hep mice. Tumorigenesis
occurs in the context of mild inflammation, low-grade fibrosis and
Pparγ-driven dyslipidemia. Subsequent analyses revealed increased
expression of c-Myc, evidently under direct regulation by AP-1 through a
conserved distal 3’ enhancer. Importantly,
c-Jun~Fra-2-induced tumors revert upon switching off
transgene expression, suggesting oncogene addiction to the
c-Jun~Fra-2 transgene. Tumors escaping reversion
maintained c-Myc and c-Myc target gene expression, likely due to
increased c-Fos. Interfering with c-Myc in established tumors using the
BET bromodomain inhibitor JQ-1 diminished liver tumor growth in
c-Jun~Fra-2 mutant mice. Thus, our data establish
c-Jun~Fra-2hep mice as a novel model
to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc
interaction as a potential target to improve HCC patient stratification
and/or therapy.