title: Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/Snail signaling.
abstract: BACKGROUND
  Oct4 and Nanog are key regulatory genes that maintain the pluripotency and self-renewal properties of embryonic stem cells. We previously reported that the two stemness markers were tightly associated with cancer progression and poor outcomes of hepatocellular carcinoma. In this study, we demonstrate that coexpression of Oct4/Nanog modulates activation of signal transducer and activator of transcription 3 (Stat3), an oncogenic transcription factor that is activated in many human malignancies including hepatocellular carcinoma (HCC), as well as the expression of Snail, a key regulator implicated in epithelial-mesenchymal transition and tumor metastasis.
  
  
  METHODS
  Oct4 and Nanog were ectopic expressed in MHCC97-L cell lines via lentiviral gene transfection. The stemness characteristics including self-renewal, proliferation, chemoresistance, and tumorigenicity were assessed. The effect of coexpression of Oct4 and Nanog on epithelial-mesenchymal transition change, and the underlying molecular signaling was investigated.
  
  
  RESULTS
  Ectopic coexpression of Oct4 and Nanog empowered MHCC97-L cells with cancer stem cell (CSC) properties, including self-renewal, extensive proliferation, drug resistance, and high tumorigenic capacity. Significantly, Oct4 and Nanog encouraged epithelial-mesenchymal transition change contributing to tumor migration, invasion/metastasis in vitro and in vivo. Following molecular mechanism investigation indicated Oct4/Nanog-regulated epithelial-mesenchymal transition change through Stat3-dependent Snail activation. Moreover, silencing Stat3 abrogates Oct4/Nanog-mediated epithelial-mesenchymal transition (EMT) change and invasion/metastasis in HCC.
  
  
  CONCLUSIONS
  We delineate Oct4 and Nanog initiate stem cell characteristics in hepatocellular carcinoma and promote epithelial-mesenchymal transition through activation of Stat3/Snail signaling. Our findings propose Stat3/Snail pathway as a novel therapeutic target for the treatment of progression and metastasis of HCC with CSC-like signatures and epithelial-mesenchymal transition phenotype.
authors: Liver Cancer Institute, Zhong Shan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China. yin.xin@zs-hospital.sh.cn.
authors: Xin
authors: X
authors: Yin
authors: Liver Cancer Institute, Zhong Shan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China. zhang.boheng@zs-hospital.sh.cn.
authors: Bo-Heng
authors: BH
authors: Zhang
authors: Liver Cancer Institute, Zhong Shan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China. 339444217@qq.com.
authors: Su-Su
authors: SS
authors: Zheng
authors: Liver Cancer Institute, Zhong Shan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China. gao.dongmei@zs-hospital.sh.cn.
authors: Dong-Mei
authors: DM
authors: Gao
authors: Liver Cancer Institute, Zhong Shan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China. qiu.shuangjian@zs-hospital.sh.cn.
authors: Shuang-Jian
authors: SJ
authors: Qiu
authors: Liver Cancer Institute, Zhong Shan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China. wu.weizhong@zs-hospital.sh.cn.
authors: Wei-Zhong
authors: WZ
authors: Wu
authors: Liver Cancer Institute, Zhong Shan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China. Ren.zhenggang@zs-hospital.sh.cn.
authors: Zheng-Gang
authors: ZG
authors: Ren
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors