Chemoprevention by Bromodomain Inhibition in a Rodent Model of Hepatocellular Carcinoma
Shen Li1, *Nourdine Hamdane2, *Frank Jühling2, *Gunisha Arora1, *Mozhdeh Sojoodi1, *Derek J Erstad1, *Michael Lanuti1, *Thomas F Baumert2, *Bryan C Fuchs1, Kenneth K Tanabe1
1Massachusetts General Hospital, Boston, MA;2Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
Introduction: Hepatocellular carcinoma (HCC) is a leading cause of mortality. The bromodomain family consists of BRD2, BRD3 and BRD4 proteins. BRD4 amplification has been implicated in HCC carcinogenesis. The hypothesis of this study is that BRD4 inhibitor JQ1 reduces cirrhosis and HCC development in a mouse model of HCC.
Methods: Male C57Bl/6 mice received an injection of diethylnitrosamine at day 15, followed by the initiation of a choline-deficient, L amino acid-defined high fat diet. This model reliably recapitulates histological and molecular features of HCC development with induction of fibrosis at 18 weeks and HCC nodules by 24 weeks. Mice were randomized to receive JQ1 or vehicle only. Livers were harvested and analyzed at 30 weeks.
Results: A significant decrease in the total of number of liver nodules after JQ1 treatment compared to vehicle control (13.3±1.5 vs. 3.6±0.9; p<0.001) was observed. Liver sections were stained by picrosirius red to assess for fibrosis. JQ1 significantly reduced collagen deposition, and this histologic observation was confirmed by reduced expression of multiple pro-fibrotic genes. A clinical prognostic HCC risk gene signature was associated with higher risks off HCC in cirrhotic patients. Inhibition of BRD4 has been shown to reverse this high risk gene signature in an in-vitro model and patient-derived ex vivo liver tissue. In this study, RNA-Seq analysis revealed that JQ1 treatment reverted the HCC gene signature from a high risk to low risk profile.
Conclusion: Overall our data supports that bromodomain inhibitors may be used to reduce fibrosis as well as prevent HCC.
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