Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc.
Proc Natl Acad Sci U S A
; 121(18): e2404188121, 2024 Apr 30.
Article
de En
| MEDLINE
| ID: mdl-38657045
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 Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 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 Bromodomain and Extra-Terminal motif 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 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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines proto-oncogènes c-myc
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Protéines proto-oncogènes c-jun
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Protéines proto-oncogènes c-fos
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Carcinome hépatocellulaire
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Facteur de transcription AP-1
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Antigène-2 apparenté à fos
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Tumeurs du foie
Limites:
Animals
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Humans
Langue:
En
Journal:
Proc Natl Acad Sci U S A
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Proc. Natl. Acad. Sci. U. S. A
/
Proceedings of the national academy of sciences of the United States of America
Année:
2024
Type de document:
Article
Pays d'affiliation:
Autriche
Pays de publication:
États-Unis d'Amérique