Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Hepatology. 2013 Jun;57(6):2480-90. doi: 10.1002/hep.26251.
Hepatocyte nuclear factor 4 alpha (HNF4α), the master regulator of hepatocyte differentiation, has been recently shown to inhibit hepatocyte proliferation by way of unknown mechanisms. We investigated the mechanisms of HNF4α-induced inhibition of hepatocyte proliferation using a novel tamoxifen (TAM)-inducible, hepatocyte-specific HNF4α knockdown mouse model. Hepatocyte-specific deletion of HNF4α in adult mice resulted in increased hepatocyte proliferation, with a significant increase in liver-to-body-weight ratio. We determined global gene expression changes using Illumina HiSeq-based RNA sequencing, which revealed that a significant number of up-regulated genes following deletion of HNF4α were associated with cancer pathogenesis, cell cycle control, and cell proliferation. The pathway analysis further revealed that c-Myc-regulated gene expression network was highly activated following HNF4α deletion. To determine whether deletion of HNF4α affects cancer pathogenesis, HNF4α knockdown was induced in mice treated with the known hepatic carcinogen diethylnitrosamine (DEN). Deletion of HNF4α significantly increased the number and size of DEN-induced hepatic tumors. Pathological analysis revealed that tumors in HNF4α-deleted mice were well-differentiated hepatocellular carcinoma (HCC) and mixed HCC-cholangiocarcinoma. Analysis of tumors and surrounding normal liver tissue in DEN-treated HNF4α knockout mice showed significant induction in c-Myc expression. Taken together, deletion of HNF4α in adult hepatocytes results in increased hepatocyte proliferation and promotion of DEN-induced hepatic tumors secondary to aberrant c-Myc activation.
肝细胞核因子 4 阿尔法（HNF4α）是肝细胞分化的主要调节因子，最近的研究表明，它通过未知的机制抑制肝细胞增殖。我们使用一种新型的他莫昔芬（TAM）诱导的、肝细胞特异性的 HNF4α 敲低小鼠模型，研究了 HNF4α 诱导的肝细胞增殖抑制的机制。成年小鼠中肝细胞特异性的 HNF4α 缺失导致肝细胞增殖增加，肝体比显著增加。我们使用基于 Illumina HiSeq 的 RNA 测序进行了全基因组基因表达变化的检测，结果表明，HNF4α 缺失后上调的基因中有相当数量与癌症发病机制、细胞周期控制和细胞增殖有关。通路分析进一步表明，c-Myc 调控的基因表达网络在 HNF4α 缺失后被高度激活。为了确定 HNF4α 的缺失是否影响癌症发病机制，我们在接受已知的肝致癌物二乙基亚硝胺（DEN）处理的小鼠中诱导 HNF4α 敲低。HNF4α 的缺失显著增加了 DEN 诱导的肝肿瘤的数量和大小。病理分析显示，HNF4α 缺失小鼠的肿瘤为分化良好的肝细胞癌（HCC）和混合 HCC-胆管癌。对 DEN 处理的 HNF4α 敲除小鼠的肿瘤和周围正常肝组织进行分析显示，c-Myc 的表达显著诱导。总之，成年肝细胞中 HNF4α 的缺失导致肝细胞增殖增加，并促进 DEN 诱导的肝肿瘤的发生，这是由于异常的 c-Myc 激活所致。
