Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc (Author copy)  

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-2 hep 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-2 hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis and Pparγ-driven dyslipidemia.