Paradis Valérie, Bièche Ivan, Dargère Delphine, Laurendeau Ingrid, Nectoux Juliette, Degott Claude, Belghiti Jacques, Vidaud Michel, Bedossa Pierre
Service d'Anatomie Pathologique and Service de Chirurgie, Hôpital Beaujon, Clichy, France.
Gastroenterology. 2003 Mar;124(3):651-9. doi: 10.1053/gast.2003.50104.
Although the pathogenesis of focal nodular hyperplasia (FNH) of the liver remains unclear, a vascular mechanism has been suspected. To gain insight into the pathogenesis of FNH, we performed a large-scale quantitative study of gene expression in FNH.
Quantitative expression level of 209 selected genes was assessed using real-time reverse-transcription polymerase chain reaction in 14 cases of FNH and compared with their expression level in 13 cases of liver cirrhosis, 4 adenomas, and 15 hepatocellular carcinomas.
Among the 7 genes, the expression of which was significantly up-regulated or down-regulated in FNH, the most informative markers for the diagnosis of FNH as assessed using the receiving operative curve and area under the curve (AUC) were angiopoietin-1 (Ang-1; AUC, 0.82) and angiopoietin-2 (Ang-2; AUC, 0.80). These 2 genes are involved in the regulation of vasculogenesis. In FNH, Ang-1 was significantly up-regulated, Ang-2 was down-regulated, and the Ang-1/Ang-2 ratio was highly and specifically increased in FNH compared with normal liver or other groups of lesions (FNH, 15.2-fold increase; HCC, 2.78; adenoma, 2.28; cirrhosis, 1.92; P < 0.01 for FNH vs. all groups, analysis of variance). Tie-2 messenger RNA, the receptor of Ang-1 and Ang-2, was detected at the same level in FNH as in normal liver. Ang-1 protein was detected on Western blot of FNH and expressed by endothelial cells of dystrophic vessels and sinusoids as shown by immunohistochemistry.
A specific increase of Ang-1/Ang-2 ratio in FNH, in the presence of the functional Tie-2 receptor, might be involved in the formation of hyperplastic and dystrophic vessels of FNH.
尽管肝局灶性结节性增生（FNH）的发病机制尚不清楚，但怀疑存在血管机制。为深入了解FNH的发病机制，我们对FNH中的基因表达进行了大规模定量研究。
采用实时逆转录聚合酶链反应评估14例FNH中209个选定基因的定量表达水平，并与13例肝硬化、4例腺瘤和15例肝细胞癌中的表达水平进行比较。
在FNH中表达显著上调或下调的7个基因中，使用接受操作曲线和曲线下面积（AUC）评估，诊断FNH最具信息量的标志物是血管生成素-1（Ang-1；AUC，0.82）和血管生成素-2（Ang-2；AUC，0.80）。这两个基因参与血管生成的调节。在FNH中，Ang-1显著上调，Ang-2下调，与正常肝脏或其他病变组相比，FNH中Ang-1/Ang-2比值显著且特异性升高（FNH升高15.2倍；肝癌升高2.78倍；腺瘤升高2.28倍；肝硬化升高1.92倍；FNH与所有组相比，P < 0.01，方差分析）。Ang-1和Ang-2的受体Tie-2信使核糖核酸在FNH中的检测水平与正常肝脏相同。在FNH的蛋白质免疫印迹中检测到Ang-1蛋白，免疫组化显示其由营养不良性血管和血窦的内皮细胞表达。
在存在功能性Tie-2受体的情况下，FNH中Ang-1/Ang-2比值的特异性升高可能参与了FNH增生性和营养不良性血管的形成。
