Merle Philippe, de la Monte Suzanne, Kim Miran, Herrmann Marc, Tanaka Shinji, Von Dem Bussche Annette, Kew Michael C, Trepo Christian, Wands Jack R
The Liver Research Center, Department of Medicine and Pathology, Brown Medical School, Providence, Rhode Island 02903, USA.
Gastroenterology. 2004 Oct;127(4):1110-22. doi: 10.1053/j.gastro.2004.07.009.
BACKGROUND & AIMS: The molecular pathogenesis of human hepatocellular carcinoma (HCC) is understood poorly. In some tumors, activation of the Wnt/beta-catenin pathway as a result of beta-catenin gene mutations has been found. However, in many other HCCs, activation of the Wnt/beta-catenin pathway has been shown in the absence of such mutations.
We previously have identified the upstream human Frizzled-7 receptor (FZD7) gene of this pathway. In the present study, a quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for FZD7 was developed and overexpression of FZD7 was detected in 90% of tumors, most of which were related to chronic hepatitis B virus infection. FZD7 also was overexpressed in the 6 HCC cell lines tested and functional analysis showed that FZD7 messenger RNA (mRNA) levels correlated with enhanced cellular motility.
Transfection of HCC cells with dominant-negative mutant constructs encoding a C-terminally truncated FZD7 protein decreased wild-type beta-catenin protein accumulation and reduced cell motility. More importantly, we observed beta-catenin accumulation in human HCC tumors containing the wild-type beta-catenin gene in the context of high-level FZD7 expression.
These observations suggest that the Wnt/beta-catenin signal transduction pathway is involved much more commonly in the molecular pathogenesis of HCC than previously recognized because FZD7 overexpression occurred early in the disease process, stabilized wild-type beta-catenin levels, and contributed to enhanced tumor cell migration.
人类肝细胞癌（HCC）的分子发病机制尚不清楚。在一些肿瘤中，已发现由于β-连环蛋白基因突变导致Wnt/β-连环蛋白信号通路激活。然而，在许多其他肝癌中，该信号通路在不存在此类突变的情况下也被激活。
我们之前已鉴定出该信号通路的上游人类卷曲蛋白-7受体（FZD7）基因。在本研究中，我们开发了一种针对FZD7的定量实时逆转录聚合酶链反应（RT-PCR）检测方法，并在90%的肿瘤中检测到FZD7过表达，其中大多数与慢性乙型肝炎病毒感染有关。FZD7在6种受试肝癌细胞系中也呈过表达，功能分析表明FZD7信使核糖核酸（mRNA）水平与增强的细胞运动性相关。
用编码C末端截短的FZD7蛋白的显性负性突变体构建体转染肝癌细胞，可减少野生型β-连环蛋白的蛋白积累并降低细胞运动性。更重要的是，我们在FZD7高表达背景下的含有野生型β-连环蛋白基因的人类肝癌肿瘤中观察到β-连环蛋白积累。
这些观察结果表明，Wnt/β-连环蛋白信号转导通路在肝癌分子发病机制中的参与程度比之前认为的更为普遍，因为FZD7过表达在疾病过程早期就已出现，稳定了野生型β-连环蛋白水平，并促进了肿瘤细胞迁移。
