title: Twist2 promotes self-renewal of liver cancer stem-like cells by regulating CD24.
abstract: Twist2 is a highly conserved basic helix-loop-helix transcription factor that plays a critical role in embryogenesis. Recent evidence has revealed that aberrant Twist2 expression contributes to tumor progression; however, the role of Twist2 in human hepatocellular carcinoma (HCC) and its underlying mechanisms remain undefined. In this report, we demonstrate that Twist2 is overexpressed in human HCC tumors. We show that ectopic expression of Twist2 induces epithelial-mesenchymal transition phenotypes, augments cell migration and invasion and colony-forming abilities in human HCC cells in vitro, and promotes tumor growth in vivo. Moreover, we found a higher percentage of CD24(+) liver cancer stem-like cells in Twist2-transduced HCC cells. Twist2-expressing cells exhibited an increased expression of stem cell markers Bmi-1, Sox2, CD24 and Nanog and an increased capacity for self-renewal. Knockdown of CD24 in HepG2/Twist2 cells decreased the levels of Sox2, pSTAT3 and Nanog, and reversed the cancer stem-like cell phenotypes induced by ectopic expression of Twist2. Furthermore, Twist2 regulated the CD24 expression by directly binding to the E-box region in CD24 promoter. Therefore, our data demonstrated that Twist2 augments liver cancer stem-like cell self-renewal in a CD24-dependent manner. Twist2-CD24-STAT3-Nanog pathway may play a critical role in regulating liver cancer stem-like cell self-renewal. The identification of the Twist2-CD24 signaling pathway provides a potential therapeutic approach to target cancer stem cells in HCCs.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China.
authors.forename: Allan Yi
authors.initials: AY
authors.lastname: Liu
authors.forename: Yao
authors.initials: Y
authors.lastname: Cai
authors.forename: Yubin
authors.initials: Y
authors.lastname: Mao
authors.forename: Yancheng
authors.initials: Y
authors.lastname: Lin
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Tiantian
authors.initials: T
authors.lastname: Wu
authors.forename: Yangmei
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Fang
authors.forename: Shuyong
authors.initials: S
authors.lastname: Lin
authors.forename: Qingzhao
authors.initials: Q
authors.lastname: Feng
authors.forename: Zhengjie
authors.initials: Z
authors.lastname: Huang
authors.forename: Tianci
authors.initials: T
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.forename: Gaoliang
authors.initials: G
authors.lastname: Ouyang
mesh_terms: D001483:Base Sequence; D051927:CD24 Antigen / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000502:physiology*
chemical_list: D051927:CD24 Antigen; D017931:DNA Primers; D012097:Repressor Proteins; C486274:TWIST2 protein, human; D051879:Twist-Related Protein 1