Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.
Cancer Cell. 2013 Jun 10;23(6):784-95. doi: 10.1016/j.ccr.2013.04.019. Epub 2013 May 30.
The incidence of cholangiocellular carcinoma (CCC) is increasing worldwide. Using a transgenic mouse model, we found that expression of the intracellular domain of Notch 1 (NICD) in mouse livers results in the formation of intrahepatic CCCs. These tumors display features of bipotential hepatic progenitor cells, indicating that intrahepatic CCC can originate from this cell type. We show that human and mouse CCCs are characterized by high expression of the cyclin E protein and identified the cyclin E gene as a direct transcriptional target of the Notch signaling pathway. Intriguingly, blocking γ-secretase activity in human CCC xenotransplants results in downregulation of cyclin E expression, induction of apoptosis, and tumor remission in vivo.
胆管细胞癌（CCC）的发病率在全球范围内呈上升趋势。我们使用转基因小鼠模型发现，Notch1 细胞内结构域（NICD）在小鼠肝脏中的表达导致肝内 CCC 的形成。这些肿瘤显示出双潜能肝祖细胞的特征，表明肝内 CCC 可以起源于这种细胞类型。我们表明，人类和小鼠 CCC 具有高 cyclin E 蛋白表达的特征，并鉴定出 cyclin E 基因是 Notch 信号通路的直接转录靶标。有趣的是，在人 CCC 异种移植中阻断 γ-分泌酶活性会导致 cyclin E 表达下调、诱导细胞凋亡和体内肿瘤消退。
