The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

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‐CreERT2 (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.

Near-infrared fluorescence imaging of hepatocellular carcinoma cells regulated by β-catenin signaling pathway

“…Consistently, we demonstrated that the increased OATP2B1 expression was induced by up-regulated HNF4α. Previous studies have reported that the increase of HNF4α expression is associated with HCC progression ( 44 , 45 ), and β-catenin signaling plays an important role in regulating HNF4α ( 46 ). Youmna Ali et al.…”

Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Unmet Questions

“…The other patient had type 2 diabetes and showed obliterative portal venopathy and incomplete septal fibrosis. In patients with hepatocellular carcinoma (HCC), it is imperative to consider the possibility of a coexisting second potential trigger of HCC as PSVD is infrequently associated with HCC, 5 and the exact etiopathogenesis of HCC in the setting of PSVD is unclear. Also, incomplete septal cirrhosis may represent regressed cirrhosis and may be unrelated to the risk factors of PSVD.…”