Gramantieri Laura, Giovannini Catia, Lanzi Arianna, Chieco Pasquale, Ravaioli Matteo, Venturi Annamaria, Grazi Gian Luca, Bolondi Luigi
Center for Applied Biomedical Research (CRBA), University of Bologna and St Orsola-Malpighi University Hospital, Bologna, Italy.
Liver Int. 2007 Sep;27(7):997-1007. doi: 10.1111/j.1478-3231.2007.01544.x.
Notch signalling is altered in several solid tumours and it plays a role in growth inhibition and apoptosis of hepatocellular carcinoma (HCC)-derived cell lines, bile duct development and hepatocyte regeneration.
This study aims to analyse the expression of Notch3, Notch4 and HES1 and HES6 as Notch-target genes in HCC, matched non-neoplastic tissue and HEPG2 cells.
Notch3 and Notch4 are not expressed in normal liver and in chronic hepatitis surrounding HCC. Cirrhotic tissue stains negative for Notch3, while Notch4 is expressed by hepatocytes at the edge of regenerative nodules and in cell planes adjacent to fibrous septa. HCC tissue displays Notch3 and Notch4 abnormal accumulation, respectively, in 78% and 68% of the cases. The endothelium of hepatic veins with neoplastic permeation is frequently Notch4 positive. An upregulation of Notch3 mRNA was found in 95% of HCCs vs cirrhosis (P=0.0001), while Notch4 mRNA was downregulated in 80% of HCCs. HES6 mRNA expression was higher in HCC tissue when compared with cirrhosis (P=0.007), paralleling Notch3 mRNA expression. The HEPG2 cell line displays high Notch3 and low Notch4 protein and mRNA levels.
These descriptive findings suggest an aberrant expression of Notch3 and Notch4 in HCC and allow the hypothesis of an activation of Notch signalling by Notch3.
Notch信号通路在多种实体瘤中发生改变，并且在肝癌（HCC）衍生细胞系的生长抑制和凋亡、胆管发育及肝细胞再生中发挥作用。
本研究旨在分析Notch3、Notch4以及作为Notch靶基因的HES1和HES6在HCC、配对的非肿瘤组织及HepG2细胞中的表达情况。
Notch3和Notch4在正常肝脏及HCC周围的慢性肝炎中不表达。肝硬化组织中Notch3染色呈阴性，而Notch4在再生结节边缘的肝细胞及与纤维间隔相邻的细胞层中表达。HCC组织中，分别有78%和68%的病例出现Notch3和Notch4异常蓄积。伴有肿瘤浸润的肝静脉内皮细胞Notch4常呈阳性。与肝硬化相比，95%的HCC中Notch3 mRNA上调（P=0.0001），而80%的HCC中Notch4 mRNA下调。与肝硬化相比，HCC组织中HES6 mRNA表达更高（P=0.007），与Notch3 mRNA表达情况相似。HepG2细胞系中Notch3蛋白和mRNA水平高，Notch4蛋白和mRNA水平低。
这些描述性结果提示HCC中Notch3和Notch4表达异常，并支持Notch3激活Notch信号通路的假说。
