Inserm, U1016, Institut Cochin, Paris, France.
CNRS, UMR8104, Paris, France.
Liver Int. 2019 Apr;39(4):727-739. doi: 10.1111/liv.14068. Epub 2019 Feb 24.
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.
We generated a Hnf4a Apc /TTR-Cre (Hnf4a/Apc ) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis.
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.
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.
肝细胞核因子-4α（HNF4α）是驱动肝脏发育和分化的关键因子，其缺失常与肝细胞癌（HCC）相关。我们最近的数据显示，β-catenin 信号激活的 HCC 中 HNF4α 水平降低。此外，通过抑制 miR-34a 增加 HNF4α 水平可减缓 β-catenin 激活的 HCC 在小鼠中的肿瘤进展。
我们构建了 Hnf4a Apc /TTR-Cre（Hnf4a/Apc）小鼠系，并评估了 Hnf4a 缺失对 HCC 发生和肝脏稳态的影响。
Hnf4a 缺失对 Apc 模型中的肿瘤起始和进展没有显著影响。然而，我们在常规动物设施中维持的 28%的 Hnf4a 小鼠中观察到一种意外表型，其表现为门脉三联体排列紊乱，特征为门脉狭窄、肝动脉和胆管数量增加且增大。这些异常的门脉结构类似于人类特发性非肝硬化性门静脉高压综合征。我们将门脉重塑的存在与 TGFβ和 BMP7 的蛋白和 mRNA 水平的升高相关联，TGFβ和 BMP7 是 TGFβ 依赖性内皮到间充质转化的关键调节因子。
这些数据表明，HNF4α 在 β-catenin 驱动的 HCC 中不起主要作用，从而表明 HNF4α 的肿瘤抑制作用要复杂得多，可能依赖于其时间表达和肿瘤背景。然而，成年肝细胞中 HNF4α 的缺失可能会导致类似于人类特发性非肝硬化性门静脉高压综合征的异常门脉结构，这可能是由内皮细胞和上皮细胞向间充质转化引起的。
