Haber B A, Chuang E, Lee W, Taub R
Division of Gastroenterology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104-6145, USA.
Hepatology. 1996 Jul;24(1):65-71. doi: 10.1002/hep.510240113.
Patients with hereditary tyrosinemia type 1 have a deficiency of fumarylacetoacetate hydrolase (FAH) and develop progressive hepatocellular dysfunction with a high risk of malignant transformation. Serum alpha-fetoprotein levels are frequently elevated in these patients; therefore, this commonly used marker of tumorigenesis is inadequate. To date, no literature exists describing the hepatic gene alterations in patients with this disease. We analyzed the expression of a panel of proliferation associated and liver-specific genes in the liver of a 33 month-old girl at the time of orthotopic liver transplantation. This study provides information that may be useful in developing markers for malignancy and understanding the pathogenesis of this disease. Gene expression patterns of two regenerating nodules and total liver from the patient with FAH deficiency were compared with control donor liver. Liver-specific and growth-induced genes with altered expression in the tyrosinemic liver included several functional classes: structural proteins (actin, thrombospondin), transcription factors (c-fos, egr-1, C/EBPalpha), liver-specific enzymes (glucose-6-phosphatase [G6Phase], and secreted factors (insulin-like growth factor binding protein 1 [GFBP-1]. Isolated macronodules demonstrated varied patterns of expression, suggesting that they do not form a homogeneous cellular environment. In the tyrosinemic liver, IGFBP-1 messenger RNA expression was high and G6Phase messenger RNA was not detectable. Although G6Phase and IGFBP-1 are coexpressed in regenerating liver, immunohistochemistry in the tyrosinemic liver demonstrated a mutually exclusive distribution for the two proteins in a tissue section with features of dysplasia. We propose that cells in these areas may have an aberrant transcription factor and growth factor "milieu" that leads to altered gene and protein expression. These molecular alterations are reflected in dysplastic histologic changes and may ultimately predispose to the development of malignancy.
1型遗传性酪氨酸血症患者缺乏延胡索酰乙酰乙酸水解酶（FAH），会出现进行性肝细胞功能障碍，并有很高的恶性转化风险。这些患者的血清甲胎蛋白水平经常升高；因此，这种常用的肿瘤发生标志物并不充分。迄今为止，尚无文献描述该疾病患者的肝脏基因改变情况。我们分析了一名33个月大女孩在原位肝移植时肝脏中一组增殖相关基因和肝脏特异性基因的表达情况。本研究提供的信息可能有助于开发恶性肿瘤标志物并了解该疾病的发病机制。将FAH缺乏患者的两个再生结节和整个肝脏的基因表达模式与对照供体肝脏进行了比较。酪氨酸血症肝脏中表达改变的肝脏特异性基因和生长诱导基因包括几个功能类别：结构蛋白（肌动蛋白、血小板反应蛋白）、转录因子（c-fos、egr-1、C/EBPα）、肝脏特异性酶（葡萄糖-6-磷酸酶[G6Phase]）和分泌因子（胰岛素样生长因子结合蛋白1[GFBP-1]）。分离出的大结节表现出不同的表达模式，表明它们没有形成均匀的细胞环境。在酪氨酸血症肝脏中，IGFBP-1信使核糖核酸表达很高，而G6Phase信使核糖核酸无法检测到。尽管G6Phase和IGFBP-1在再生肝脏中共同表达，但酪氨酸血症肝脏的免疫组织化学显示，在具有发育异常特征的组织切片中，这两种蛋白质呈相互排斥的分布。我们提出，这些区域的细胞可能具有异常的转录因子和生长因子“环境”，导致基因和蛋白质表达改变。这些分子改变反映在发育异常的组织学变化中，最终可能易导致恶性肿瘤的发生。
