肝细胞癌（HCC）可表现出细胞异质性，胚胎干细胞相关的基因在部分低低分化肿瘤的癌细胞中过度表达。尽管如此，尚不清楚这类癌细胞能否及怎样促进肿瘤发生进展。因此，我们的研究数据显示癌细胞中多潜能转录因子Nanog与HCC的恶劣临床转归相关。我们用Nanog启动子作为标志系统成功分离Nanog阳性（Nanog^Pos）细胞的小亚群。我们证明Nanog^Pos细胞的自我更新、克隆形成及肿瘤发生能力得到增强，这种增强与用于确定肿瘤干细胞（CSCs）的重要标志物相关。Nanog^Pos CSCs可在体内及体外环境中分化为成熟肿瘤细胞。另外，我们发现Nanog^Pos 的CSCs对化疗耐药（如索菲拉尼及顺铂），且具有强大的肿瘤侵袭及转移能力。降低Nanog^Pos CSCs的Nanog表达可减弱自我更新，伴随干细胞相关基因表达的降低及成熟肝细胞相关基因表达的增加。增高Nanog表达可恢复Nanog阴性（Nanog^Neg）细胞的自我更新。此外，我们还发现胰岛素样受体生长因子（IGF）2及IGF受体（IGF1R）在Nanog^Neg CSCs中高表达。降低Nanog^Pos CSCs中Nanog表达能够抑制IGF1R表达，增强Nanog^Neg细胞中Nanog表达可提高IGF1R表达。特异性IGF1R信号抑制剂能够显著抑制自我更新及Nanog表达，提示IGF1R信号参予了Nanog相关的自我更新。结论：这些研究数据显示Nanog可作为HCC中CSCs的全新生物学标记，且Nanog可以通过IGF1R信号通路在维持CSCs自我更新中扮演重要作用。

                                       重庆西南医院感染科 朱鹏 王宇明摘译

                                   本文来源于[HEPATOLOGY ,2012;56:1004-1014]

Nanog Regulates Self-Renewal of Cancer Stem Cells Through the Insulin-Like Growth Factor Pathway in Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell–related genes are preferentially overexpressed in a fraction of cancer cells of poorly differ-entiated 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 out-come 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).Nanog ^Pos CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. . In addition, we found that Nanog^Pos 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 Nanog^Pos CSCs could decrease self-renewal accompanied  with  decreased  expression  of  stem-cell–related  genes  and  increased  expression  of mature hepatocyte-related genes. Over expression of Nanog in Nanog^Neg cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF recep-tor (IGF1R) were up-regulated in Nanog^Pos CSCs. Knock-down expression of Nanog in Nanog^Pos CSCs  inhibited  the  expression  of  IGF1R,  and  overexpression  of  Nanog  in Nanog ^Neg 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.(HEPATOLOGY 2012;56:1004-1014)

（由第三军医大学西南医院钱程及卞修武教授领衔开展的一项最新研究）点击下载此文件