Wang Ronghua, Sun Qian, Wang Peng, Liu Man, Xiong Si, Luo Jing, Huang Hai, Du Qiang, Geller David A, Cheng Bin
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Oncotarget. 2016 Feb 2;7(5):5754-68. doi: 10.18632/oncotarget.6805.
Human hepatocellular carcinoma (HCC) is driven and maintained by liver cancer stem cells (LCSCs) that display stem cell properties. These LCSCs are promoted by the intersecting of Notch and Wnt/β-Catenin signaling pathways. In this study, we demonstrate that LCSCs with markers CD90, CD24, CD13, and CD133 possess stem properties of self-renewal and tumorigenicity in NOD/SCID mice. The increased expression of these markers was correlated with advanced disease stage, larger tumors, and worse overall survival in 61 HCC cases. We also found that both Notch and Wnt/β-catenin signaling pathways played important roles in increasing the stem-ness characteristics of LCSCs. Our data suggested that Notch1 was downstream of Wnt/β-catenin. The active form of Notch1 intracellular domain (NICD) expression depended on Wnt/β-catenin pathway activation. Moreover, Notch1 negatively contributed to Wnt/β-catenin signaling modulation. Knock down of Notch1 with lentivirus N1ShRNA up-regulated the active form of β-catenin. Ectopic expression of NICD with LV-Notch1 in LCSCs attenuated β-catenin/TCF dependent luciferase activity significantly. In addition, there was a non-proteasome mediated feedback loop between Notch1 and Wnt/β-catenin signaling in LCSCs. The central role of Notch and the Wnt/β-catenin signaling pathway in LCSCs may provide an attractive therapeutic strategy against HCC.
人类肝细胞癌（HCC）由具有干细胞特性的肝癌干细胞（LCSCs）驱动并维持。Notch信号通路与Wnt/β-连环蛋白信号通路的交叉促进了这些LCSCs的产生。在本研究中，我们证明具有CD90、CD24、CD13和CD133标记的LCSCs在NOD/SCID小鼠中具有自我更新和致瘤性的干细胞特性。在61例HCC病例中，这些标记物表达的增加与疾病晚期、肿瘤较大和总体生存率较差相关。我们还发现Notch信号通路和Wnt/β-连环蛋白信号通路在增加LCSCs的干性特征方面都发挥了重要作用。我们的数据表明Notch1在Wnt/β-连环蛋白的下游。Notch1细胞内结构域（NICD）的活性形式的表达依赖于Wnt/β-连环蛋白信号通路的激活。此外，Notch1对Wnt/β-连环蛋白信号转导起负向调节作用。用慢病毒N1ShRNA敲低Notch1可上调β-连环蛋白的活性形式。在LCSCs中用LV-Notch1异位表达NICD可显著减弱β-连环蛋白/TCF依赖性荧光素酶活性。此外，在LCSCs中，Notch1与Wnt/β-连环蛋白信号之间存在非蛋白酶体介导的反馈环。Notch信号通路和Wnt/β-连环蛋白信号通路在LCSCs中的核心作用可能为HCC提供一种有吸引力的治疗策略。
