title: Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma.
abstract: 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). 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. Overexpression of Nanog in Nanog(Neg) cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Shan
authors.forename: Junjie
authors.initials: J
authors.lastname: Shen
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Xia
authors.forename: Chuan
authors.initials: C
authors.lastname: Xu
authors.forename: Guangjie
authors.initials: G
authors.lastname: Duan
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Xu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Ma
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.forename: Qianzhen
authors.initials: Q
authors.lastname: Zhang
authors.forename: Leina
authors.initials: L
authors.lastname: Ma
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Senlin
authors.initials: S
authors.lastname: Xu
authors.forename: Xiaochu
authors.initials: X
authors.lastname: Yan
authors.forename: Ping
authors.initials: P
authors.lastname: Bie
authors.forename: Youhong
authors.initials: Y
authors.lastname: Cui
authors.forename: Xiu-wu
authors.initials: XW
authors.lastname: Bian
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D017526:Receptor, IGF Type 1