Chiara Sartor1,2,3,4, Laura Bachelot1,2,3,4, Cécile Godard1,2,3,4, Franck Lager1,2,3,5, Gilles Renault1,2,3,5, Frank J Gonzalez6, Christine Perret1,2,3,4, Angélique Gougelet1,2,3,4, Sabine Colnot1,2,3,4. 1. Inserm, U1016, Institut Cochin, Paris, France. 2. CNRS, UMR8104, Paris, France. 3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 4. Equipe labellisée LNCC, Paris, France. 5. Plateforme Imageries du Vivant - PIV, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 6. Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland.
Abstract
BACKGROUND & AIMS: Loss of hepatocyte nuclear factor-4α (HNF4α), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4α level was decreased in mouse and human HCCs with activated β-catenin signalling. In addition, increasing HNF4α level by miR-34a inhibition slowed tumour progression of β-catenin-activated HCC in mice. METHODS: We generated a Hnf4aflox/flox/ Apcflox/flox /TTR-CreERT 2 (Hnf4a/Apc∆Hep ) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis. RESULTS: There was no significant impact of Hnf4a disruption on tumour onset and progression in Apc∆Hep model. However, we observed an unexpected phenotype in 28% of Hnf4a∆Hep mice maintained in a conventional animal facility, which presented disorganized portal triads, characterized by stenosis of the portal vein and increased number and size of hepatic arteries and bile ducts. These abnormal portal structures resemble the human idiopathic non-cirrhotic portal hypertension syndrome. We correlated the presence of portal remodelling with a higher expression of protein and mRNA levels of TGFβ and BMP7, a key regulator of the TGFβ-dependent endothelial-to-mesenchymal transition. CONCLUSION: These data demonstrate that HNF4α does not play a major role during β-catenin-driven HCC, thus revealing that the tumour suppressor role of HNF4α is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4α loss in adult hepatocytes could induce abnormal portal structures resembling the human idiopathic non-cirrhotic portal hypertension syndrome, which may result from endothelial- and epithelial-to-mesenchymal transitions.
BACKGROUND & AIMS: Loss of hepatocyte nuclear factor-4α (HNF4α), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4α level was decreased in mouse and humanHCCs with activated β-catenin signalling. In addition, increasing HNF4α level by miR-34a inhibition slowed tumour progression of β-catenin-activated HCC in mice. METHODS: We generated a Hnf4aflox/flox/ Apcflox/flox /TTR-CreERT 2 (Hnf4a/Apc∆Hep ) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis. RESULTS: There was no significant impact of Hnf4a disruption on tumour onset and progression in Apc∆Hep model. However, we observed an unexpected phenotype in 28% of Hnf4a∆Hep mice maintained in a conventional animal facility, which presented disorganized portal triads, characterized by stenosis of the portal vein and increased number and size of hepatic arteries and bile ducts. These abnormal portal structures resemble the human idiopathic non-cirrhotic portal hypertension syndrome. We correlated the presence of portal remodelling with a higher expression of protein and mRNA levels of TGFβ and BMP7, a key regulator of the TGFβ-dependent endothelial-to-mesenchymal transition. CONCLUSION: These data demonstrate that HNF4α does not play a major role during β-catenin-driven HCC, thus revealing that the tumour suppressor role of HNF4α is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4α loss in adult hepatocytes could induce abnormal portal structures resembling the human idiopathic non-cirrhotic portal hypertension syndrome, which may result from endothelial- and epithelial-to-mesenchymal transitions.
Authors: Vesna S Stanulović; Irene Kyrmizi; Marianna Kruithof-de Julio; Maarten Hoogenkamp; Jacqueline L M Vermeulen; Jan M Ruijter; Iannis Talianidis; Theodorus B M Hakvoort; Wouter H Lamers Journal: Hepatology Date: 2007-02 Impact factor: 17.425
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