Identification of T-cell factor-4 isoforms that contribute to the malignant phenotype of hepatocellular carcinoma cells.
The Wnt/β-catenin signaling pathway is frequently activated in hepatocellular carcinoma (HCC). Downstream signaling events involving the Wnt/β-catenin cascade occur through T-cell factor (TCF) proteins. The human TCF-4 gene is composed of 17 exons with multiple alternative splicing sites. However, the role of different TCF-4 isoforms in the pathogenesis of HCC is unknown. The purpose of this study was to identify and characterize TCF-4 isoforms in HCC. We identified 14 novel TCF-4 isoforms from four HCC cell lines. Functional analysis following transfection and expression in HCC cells revealed distinct effects on the phenotype. The TCF-4J isoform expression produced striking features of malignant transformation characterized by high cell proliferation rate, migration and colony formation even though its transcriptional activity was low. In contrast, the TCF-4K isoform displayed low TCF transcriptional activity; cell proliferation rate and colony formation were reduced as well. Interestingly, TCF-4J and TCF-4K differed by only five amino acids (the SxxSS motif). Thus, these studies suggest that conserved splicing motifs may have a major influence on the transcriptional activity and functional properties of TCF-4 isoforms and alter the characteristics of the malignant phenotype.
Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Orkhontuya
O
Tsedensodnom
Hironori
H
Koga
Stephen A
SA
Rosenberg
Sarah B
SB
Nambotin
John J
JJ
Carroll
Jack R
JR
Wands
Miran
M
Kim
D017398:Alternative Splicing; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin
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