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Published on: October 27, 2020
CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-beta signaling
1Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-beta (TGF-beta) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-beta-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-beta signaling or underlying mechanism of the expression of CEAs has not yet been clarified. In this study, we investigated the specific CEAs targeted by the TGF-beta signaling pathway. In nine human gastric cancer cell lines examined, TGF-beta-responsive cell lines showed positive expression of CEAs. Expression patterns of CEA proteins correlated well with the level of CEA (CEACAM5) and CEACAM6 transcripts in these cell lines, but CEACAM1 expression was not observed in all of these cells. To investigate the role of TGF-beta signaling in CEA expression, we selected two TGF-beta unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-beta type II receptor and SNU484 cells that express low to undetectable level of the TGF-beta pathway intermediate protein, Smad3. Restoration of TGF-beta signaling in these cells induced expression of the CEAs and increased activity of both CEA (CEACAM5) and CEACAM6 promoters. CEA expression was observed in the epithelium of the stomach of wild-type mice, but was markedly decreased in Smad3 null mice. These findings suggest that CEA (CEACAM5) and CEACAM6 are major target genes for Smad3-mediated TGF-beta signaling.
Insights
Transforming growth factor-beta (TGF-beta) signaling activates carcinoembryonic antigen (CEA) family members, specifically CEACAM5 and CEACAM6, in gastric cancer cells. This pathway is crucial for CEA expression, impacting cell adhesion and differentiation.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The carcinoembryonic antigen (CEA) family comprises diverse glycoproteins involved in cell adhesion and differentiation.
- Transforming growth factor-beta (TGF-beta) signaling is known to stimulate CEA secretion, but specific targets and mechanisms remain unclear.
Purpose of the Study:
- To identify specific CEAs regulated by TGF-beta signaling.
- To elucidate the mechanism underlying TGF-beta-induced CEA expression in gastric cancer.
Main Methods:
- Analysis of CEA expression in nine human gastric cancer cell lines.
- Investigating TGF-beta signaling restoration in unresponsive cell lines (SNU638, SNU484).
- Assessing CEACAM5 and CEACAM6 promoter activity and in vivo expression in Smad3 null mice.
Main Results:
- TGF-beta-responsive gastric cancer cells exhibited positive CEA expression.
- Restoring TGF-beta signaling induced CEACAM5 and CEACAM6 expression and promoter activity.
- CEA expression was reduced in Smad3 null mice, indicating Smad3's role.
Conclusions:
- CEACAM5 and CEACAM6 are identified as major target genes of Smad3-mediated TGF-beta signaling.
- TGF-beta signaling plays a significant role in regulating CEA expression in gastric cancer.
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