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 Hnf4a Apc /TTR-Cre (Hnf4a/Apc ) 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 model. However, we observed an unexpected phenotype in 28% of Hnf4a 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387933PMC
http://dx.doi.org/10.1111/liv.14068DOI Listing

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