title: Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers.
abstract: Liver cancers, including hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs) are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4 (SALL4), a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC, and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4's expression results in changes in proliferation versus differentiation in human HCC cell lines in vitro and in vivo in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used for gain- and loss-of-function analyses in the cell lines. Significant growth inhibition in vitro and in vivo, accompanied by an increase in differentiation occurred with down-regulation of SALL4. Overexpression of SALL4 resulted in increased cell proliferation in vitro, correlating with an increase in expression of cytokeratin19 (CK19), epithelial cell adhesion molecules (EpCAM), and adenosine triphosphate (ATP)-binding cassette-G2 (ABCG2).
  
  
  CONCLUSIONS
  SALL4's expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Oikawa
authors.forename: Akihide
authors.initials: A
authors.lastname: Kamiya
authors.forename: Mikio
authors.initials: M
authors.lastname: Zeniya
authors.forename: Hiromi
authors.initials: H
authors.lastname: Chikada
authors.forename: Ahn Dong
authors.initials: AD
authors.lastname: Hyuck
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Eliane
authors.initials: E
authors.lastname: Wauthier
authors.forename: Hisao
authors.initials: H
authors.lastname: Tajiri
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Lola M
authors.initials: LM
authors.lastname: Reid
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011379:Prognosis; D014157:Transcription Factors / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D056742:Cyclin D2; D004268:DNA-Binding Proteins; C472575:SALL4 protein, human; C509167:Sall4 protein, mouse; D014157:Transcription Factors; D019938:Cyclin D1