title: NANOG promotes liver cancer cell invasion by inducing epithelial-mesenchymal transition through NODAL/SMAD3 signaling pathway.
abstract: NANOG is a major transcription factor essential to the stem cell self-renewal and is associated with tumor malignancy, but the NANOG signaling in cancer metastasis is still elusive. In this study, we determined the expression of NANOG in hepatocellular carcinoma (HCC) and investigated its underlying mechanism in the metastasis of HCC. The expression levels of NANOG were examined in tumor tissues by immunohistochemistry. Functional effect of NANOG was investigated both in vivo and in vitro. Our data shows that high level of NANOG expression correlates with metastasis and low survival rate in HCC. HCC cells overexpressing NANOG are characterized by active epithelial-mesenchymal transition (EMT), and exhibit increased ability of invasion, soft agar colonization, sphere formation and drug resistance, whereas SB-431542, an antagonist of activin receptor-like kinase (ALK) receptors, attenuates EMT and invasion of HCC cells. NANOG activates NODAL and CRIPTO-1 to promote SMAD3 phosphorylation and SNAIL expression. The transcriptional activity of NODAL gene is dependent on two NANOG binding motifs in its promoter region. This study shows a significant correlation between the NANOG expression and the expression of NODAL, P-SMAD3 or SNAIL, and the combination of NANOG and P-SMAD3 is a potential predictor of poor prognosis of HCC. Additionally, cells in the tumor edge area displays higher NANOG expression than cells in the tumor center. These results present novel mechanistic insight into an important role of NANOG in HCC metastasis, and suggest a potential application of NANOG in HCC prognosis and treatment.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Sun
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Gao
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Kang
authors.forename: Cun
authors.initials: C
authors.lastname: Wang
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.forename: Xue
authors.initials: X
authors.lastname: Qin
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yin-Kun
authors.initials: YK
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005500:Follow-Up Studies; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C486780:NANOG protein, human; C526007:NODAL protein, human; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D055457:Nodal Protein; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C070636:TDGF1 protein, human