The VTI1A-TCF4 colon cancer fusion protein is a dominant negative regulator of Wnt signaling and is transcriptionally regulated by intestinal homeodomain factor CDX2.

Tytuł:: The VTI1A-TCF4 colon cancer fusion protein is a dominant negative regulator of Wnt signaling and is transcriptionally regulated by intestinal homeodomain factor CDX2.
Autorzy:: Davidsen J; Department of Science and Environment, Roskilde University, Roskilde, Denmark.; Department of Surgery, Zealand University Hospital, Roskilde, Denmark.
Larsen S; Department of Science and Environment, Roskilde University, Roskilde, Denmark.; Department of Clinical Immunology, Naestved Hospital, Naestved, Denmark.
Coskun M; Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
Gögenur I; Department of Surgery, Zealand University Hospital, Roskilde, Denmark.
Dahlgaard K; Department of Science and Environment, Roskilde University, Roskilde, Denmark.
Bennett EP; Copenhagen Center for Glycomics, Department of Odontology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Troelsen JT; Department of Science and Environment, Roskilde University, Roskilde, Denmark.
Źródło:: PloS one [PLoS One] 2018 Jul 05; Vol. 13 (7), pp. e0200215. Date of Electronic Publication: 2018 Jul 05 (Print Publication: 2018).
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: San Francisco, CA : Public Library of Science
MeSH Terms:: Wnt Signaling Pathway*
CDX2 Transcription Factor/*genetics
Colonic Neoplasms/*genetics
Oncogene Proteins, Fusion/*genetics
Qb-SNARE Proteins/*genetics
Transcription Factor 7-Like 2 Protein/*genetics
Binding Sites ; CDX2 Transcription Factor/metabolism ; Cell Line, Tumor ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Genes, Reporter ; Humans ; Intestines/pathology ; Oncogene Proteins, Fusion/metabolism ; Promoter Regions, Genetic ; Qb-SNARE Proteins/metabolism ; Transcription Factor 7-Like 2 Protein/metabolism ; beta Catenin/metabolism
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Substance Nomenclature:: 0 (CDX2 Transcription Factor)
0 (CDX2 protein, human)
0 (DNA-Binding Proteins)
0 (Oncogene Proteins, Fusion)
0 (Qb-SNARE Proteins)
0 (TCF7L2 protein, human)
0 (Transcription Factor 7-Like 2 Protein)
0 (VTI1A protein, human)
0 (beta Catenin)
Entry Date(s):: Date Created: 20180706 Date Completed: 20190103 Latest Revision: 20190103
Update Code:: 20240105
PubMed Central ID:: PMC6033461
DOI:: 10.1371/journal.pone.0200215
PMID:: 29975781
: Czasopismo naukowe

Pełny tekst

Sequencing of primary colorectal tumors has identified a gene fusion in approximately 3% of colorectal cancer patients of the VTI1A and TCF7L2 genes, encoding a VTI1A-TCF4 fusion protein containing a truncated TCF4. As dysregulation of the Wnt signaling pathway is associated with colorectal cancer development and progression, the functional properties and transcriptional regulation of the VTI1A-TCF4 fusion protein may also play a role in these processes. Functional characteristics of the VTI1A-TCF4 fusion protein in Wnt signaling were analyzed in NCI-H508 and LS174T colon cancer cell lines. The NCI-H508 cell line, containing the VTI1A-TCF7L2 fusion gene, showed no active Wnt signaling, and overexpression of the VTI1A-TCF4 fusion protein in LS174T cells along with a Wnt signaling luciferase reporter plasmid showed inhibition of activity. The transcriptional regulation of the VTI1A-TCF4 fusion gene was investigated in LS174T cells where the activity of the VTI1A promoter was compared to that of the TCF7L2 promoter, and the transcription factor CDX2 was analyzed for gene regulatory activity of the VTI1A promoter through luciferase reporter gene assay using colon cancer cell lines as a model. Transfection of LS174T cells showed that the VTI1A promoter is highly active compared to the TCF7L2 promoter, and that CDX2 activates transcription of VTI1A. These results suggest that the VTI1A-TCF4 fusion protein is a dominant negative regulator of the Wnt signaling pathway, and that transcription of VTI1A is activated by CDX2.
Competing Interests: The authors have declared that no competing interests exist.

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