Notch and Wnt/β-catenin signaling pathway play important roles in activating liver cancer stem cells.
Notch and Wnt/β-catenin signaling pathway play important roles in activating liver cancer stem cells.
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Notch和Wnt/β-catenin信号通路在激活肝癌干细胞中发挥重要作用。
DOI：
10.18632/oncotarget.6805
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发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Cheng B
中科院分区：
文献类型：
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作者：
Wang R;Sun Q;Wang P;Liu M;Xiong S;Luo J;Huang H;Du Q;Geller DA;Cheng B
人肝细胞癌（HCC）由显示干细胞特性的肝癌干细胞（LCSC）驱动和维持。这些LCSC通过Notch和Wnt/β-Catenin信号通路的交叉而促进。在这项研究中，我们证明，LCSC与标志物CD 90，CD 24，CD 13，和CD 133具有干细胞的自我更新和致瘤性在NOD/SCID小鼠。在61例HCC病例中，这些标志物的表达增加与疾病分期、肿瘤较大和总生存率较差相关。我们还发现Notch和Wnt/β-catenin信号通路在增加LCSC的干细胞特性中起重要作用。我们的数据表明Notch 1位于Wnt/β-catenin的下游。Notch 1胞内结构域（NICD）的表达依赖于Wnt/β-catenin通路的激活。此外，Notch 1对Wnt/β-catenin信号通路的调节起负性作用。用慢病毒N1ShRNA敲低Notch 1可上调β-catenin的活性形式。在LCSC中具有LV-Notch 1的NICD的异位表达显著减弱β-连环蛋白/TCF依赖性荧光素酶活性。此外，LCSC中Notch 1和Wnt/β-catenin信号之间存在非蛋白酶体介导的反馈环。Notch和Wnt/β-catenin信号通路在LCSC中的中心作用可能提供针对HCC的有吸引力的治疗策略。
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.