The concomitant loss of APC and HNF4? in adult hepatocytes does not contribute to hepatocarcinogenesis driven by ?-catenin activation.

ABSTRACT: BACKGROUND & AIMS:Loss of hepatocyte nuclear factor-4? (HNF4?), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4? level was decreased in mouse and human HCCs with activated ?-catenin signalling. In addition, increasing HNF4? level by miR-34a inhibition slowed tumour progression of ?-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 TGF? and BMP7, a key regulator of the TGF?-dependent endothelial-to-mesenchymal transition. CONCLUSION:These data demonstrate that HNF4? does not play a major role during ?-catenin-driven HCC, thus revealing that the tumour suppressor role of HNF4? is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4? 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.

SUBMITTER: Sartor C 

PROVIDER: S-EPMC7387933 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature