CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway.
Invasion of colorectal carcinomas (CC) is characterized by nuclear accumulation of beta-catenin, a key component of the Wnt pathway, in scattered tumor cells. beta-catenin acts in cooperation with T-cell factor (Tcf) HMG-box transcription factors as a transcriptional activator of genes involved in tumor progression. Overexpression of CD97, a molecule that correlates with dedifferentiation and tumor stage in CC, parallels to nuclear translocation of beta-catenin. Here, we investigated whether CD97 is a direct beta-catenin/Tcf target gene. SW480 CC cells were used to mimic the phenotypical switch between central and invasive tumor areas. We demonstrate two-fold higher CD97 expression and nuclear beta-catenin accumulation in cells grown at low density compared to cells cultured at high density, showing membrane-associated beta-catenin. This suggests that CD97 expression correlates with the cellular localization of beta-catenin. However, CD97 mRNA expression levels were not affected by Tcf-1 or Tcf-4 as determined in inducible dominant-negative (dn) Tcf CC cell lines. Furthermore, co-expression of wildtype (wt) or S33A mutated beta-catenin with Tcf-4 did not influence CD97 promoter activity. Inhibition of glycogen synthase kinase (GSK)-3beta, a negative regulator of the canonical Wnt pathway, had no influence on CD97 expression levels. In summary, enhanced CD97 expression in CC cells is regulated independent of beta-catenin/Tcf-4, and is thus not a direct target of the canonical Wnt pathway.
Wobus
Manja
M
Department of Surgery, Research Laboratories, The University of Leipzig, Leipzig, Germany.
Huber
Otmar
O
Hamann
Jörg
J
Aust
Gabriela
G
D015703:Antigens, CD / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
C095004:ADGRE5 protein, human; D015703:Antigens, CD; D008562:Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D051176:beta Catenin