title: Loss of exon 4 in a human T-cell factor-4 isoform promotes hepatic tumourigenicity.
abstract: BACKGROUND
  T-cell factor (TCF) proteins represent key transcription factors that activate Wnt/β-catenin signalling. We have reported that a pair of TCF-4 isoforms (TCF-4C and TCF-4D) exhibit differential TCF transcriptional activity in hepatocellular carcinoma (HCC) cells, although their structure differs by only the presence (TCF-4D) or absence (TCF-4C) of exon 4.
  
  
  OBJECTIVE
  To demonstrate a regulatory role of exon 4 in HCC development.
  
  
  METHODS
  TCF-4C and TCF-4D expression profiles were examined in 27 pairs of human HCC and adjacent liver tissues. The functional role of the TCF-4 isoforms was evaluated in OUMS-29 (an immortalized hepatocyte-derived) and HAK-1A (a well-differentiated HCC) cell lines using stable clones overexpressing the TCF-4 isoforms.
  
  
  RESULTS
  TCF-4C was significantly upregulated in HCC tissues compared with corresponding peritumour and normal liver tissues; in contrast, there was no difference in TCF-4D expression. TCF-4C clones derived from both cell lines exhibited increased TCF activity, Wnt-responsive target genes, cell proliferation, cell cycle progression and resistance to chemotherapeutic drugs compared with TCF-4D clones. Capability of cell migration and colony formation was significantly higher in TCF-4C than TCF-4D clones. In a nude mice xenograft model, the HAK-1A-derived TCF-4C clone rapidly developed tumours compared with the TCF-4D clone. TCF-4C clone-derived tumours exhibited upregulation of Wnt-responsive target genes compared with the slow developing and small TCF-4D-derived tumours.
  
  
  CONCLUSIONS
  These results demonstrate that the TCF-4C isoform lacking exon 4 is associated with a malignant phenotype compared with the exon 4-harbouring TCF-4D isoform, indicating that exon 4 of TCF-4 plays a prominent role in HCC development.
authors: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors: Yoshito
authors: Y
authors: Tomimaru
authors: Chelsea Q
authors: CQ
authors: Xu
authors: Sarah B
authors: SB
authors: Nambotin
authors: Tao
authors: T
authors: Yan
authors: Jack R
authors: JR
authors: Wands
authors: Miran
authors: M
authors: Kim
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D005091:Exons / Q000235:genetics; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein
keywords: T-cell factor-4; Wnt; exon 4; hepatocellular carcinoma; isoform
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