癌症干细胞
癌症研究
干细胞
同源盒蛋白纳米
生长因子
胰岛素样生长因子
肝细胞癌
内科学
生物
肿瘤科
癌症
细胞生物学
医学
诱导多能干细胞
胚胎干细胞
生物化学
基因
受体
作者
Juanjuan Shan,Junjie Shen,Limei Liu,Feng Xia,Chuan Xu,Guangjie Duan,Yanmin Xu,Qinghua Ma,Zhi Yang,Qianzhen Zhang,Leina Ma,Jia Liu,Senlin Xu,Xiaochu Yan,Ping Bie,You‐Hong Cui,Xiu‐Wu Bian,Cheng Qian
出处
期刊:Hepatology
[Wiley]
日期:2012-04-03
卷期号:56 (3): 1004-1014
被引量:279
摘要
Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell–related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). NanogPos CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that NanogPos CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in NanogPos CSCs could decrease self-renewal accompanied with decreased expression of stem-cell–related genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in NanogNeg cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in NanogPos CSCs. Knock-down expression of Nanog in NanogPos CSCs inhibited the expression of IGF1R, and overexpression of Nanog in NanogNeg cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal. Conclusion : These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self-renewal of CSCs through the IGF1R-signaling pathway.
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