Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

Oncogene volume 27, pages 675–683 (2008)Cite this article

Abstract

The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-β (TGF-β) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-β-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-β 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-β signaling pathway. In nine human gastric cancer cell lines examined, TGF-β-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-β signaling in CEA expression, we selected two TGF-β unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-β type II receptor and SNU484 cells that express low to undetectable level of the TGF-β pathway intermediate protein, Smad3. Restoration of TGF-β 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-β signaling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

CEA:

carcinoembryonic antigen

ChIP:

chromatin immunoprecipitation assay

TβRII:

TGF-β type II receptor

TGF-β:

transforming growth factor-β

References

  • Benchimol S, Fuks A, Jothy S, Beauchemin N, Shirota K, Stanners CP . (1989). Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 57: 327–334.

    Article  CAS  PubMed  Google Scholar 

  • Bessa X, Elizalde JI, Mitjans F, Pinol V, Miquel R, Panes J et al. (2002). Leukocyte recruitment in colon cancer: role of cell adhesion molecules, nitric oxide, and transforming growth factor β1. Gastroenterology 122: 1122–1132.

    Article  CAS  PubMed  Google Scholar 

  • Chakrabarty S, Tobon A, Varani J, Brattain MG . (1998). Induction of carcinoembryonic antigen secretion and modulation of protein secretion/expression and fibronectin/laminin expression in human colon carcinoma cells by transforming growth factor-β. Cancer Res 48: 4059–4064.

    Google Scholar 

  • Chang J, Park K, Bang YJ, Kim WS, Kim D, Kim SJ . (1997). Expression of transforming growth factor β type II receptor reduces tumorigenicity in human gastric cancer cells. Cancer Res 57: 2856–2859.

    CAS  PubMed  Google Scholar 

  • Chevinsky AH . (1991). CEA in tumors of other than colorectal origin. Semin Surg Oncol 7: 162–166.

    Article  CAS  PubMed  Google Scholar 

  • Ergun S, Kilik N, Ziegeler G, Hansen A, Nollau P, Götze J et al. (2000). CEA-related cell adhesion molecule 1: a potent angiogenic factor and a major effector of vascular endothelial growth factor. Mol Cell 5: 311–320.

    Article  CAS  PubMed  Google Scholar 

  • Feng XH, Liang YY, Liang M, Zhai W, Lin X . (2002). Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B). Mol Cell 9: 133–143.

    Article  CAS  PubMed  Google Scholar 

  • Gold P, Freedman SO . (1965). Specific carcinoembryonic antigens of the human digestive system. J Exp Med 122: 467–481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hammarström S . (1999). The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 9: 67–81.

    Article  PubMed  Google Scholar 

  • Han SU, Kim HT, Seong DH, Kim YS, Park YS, Bang Y-J et al. (2004). Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer. Oncogene 23: 1333–1341.

    Article  CAS  PubMed  Google Scholar 

  • Heldin CH, Miyazono K, ten Dijke P . (1997). TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465–471.

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Hardy JD, Sun Y, Shively JE . (1999). Essential role of biliary glycoprotein (CD66a) in morphogenesis of the human mammary epithelial cell line MCF10F. J Cell Sci 112: 4193–4205.

    CAS  PubMed  Google Scholar 

  • Ignotz RA, Massague J . (1987). Cell adhesion protein receptors as targets for transforming growth factor-β action. Cell 51: 189–197.

    Article  CAS  PubMed  Google Scholar 

  • Ilantzis C, DeMarte L, Screaton RA, Stanners CP . (2002). Deregulated expression of the human tumor marker CEA and CEA family member CEACAM6 disrupts tissue architecture and blocks colonocyte differentiation. Neoplasia 4: 151–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kammerer R, Hahn S, Singer BB, Luo JS, von Kleist S . (1998). Biliary glycoprotein (CD66a), a cell adhesion molecule of the immunoglobulin superfamily, on human lymphocytes: structure, expression and involvement in T cell activation. Eur J Immunol 28: 3664–3674.

    Article  CAS  PubMed  Google Scholar 

  • Kammerer R, Stober D, Singer BB, brink B, Reimann J . (2001). Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J Immunol 166: 6537–6544.

    Article  CAS  PubMed  Google Scholar 

  • Kammerer R, von Kleist S . (1994). The carcinoembryonic antigen (CEA) modulates effector-target cell interaction by binding to activated lymphocytes. Int J Cancer 57: 341–347.

    Article  CAS  PubMed  Google Scholar 

  • Kang SH, Bang YJ, Jong HS, Seo JY, Kim KN, Kim S-J . (1999). Rapid induction of p21WAF1 but delayed down-regulation of Cdc25A in the TGF-β-induced cell cycle arrest of gastric carcinoma cells. Br J Cancer 80: 1144–1149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim DY, Kim HR, Shim JH, Park CS, Kim SK, Kim YJ . (2000). Significance of serum and tissue carcinoembryonic antigen for the prognosis of gastric carcinoma patients. J Surg Oncol 74: 185–192.

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Kaye FJ, Henslee JG, Shively JE, Park JG, Lai SL et al. (1992). Expression of carcinoembryonic antigen and related genes in lung and gastrointestinal cancers. Int J Cancer 52: 718–725.

    Article  CAS  PubMed  Google Scholar 

  • Kim S-J, Im Y-H, Markowitz SD, Bang Y-J . (2000). Molecular mechanisms of inactivation of TGF-β receptors during carcinogenesis. Cytokine Growth Factor Rev 11: 159–168.

    Article  CAS  PubMed  Google Scholar 

  • Kuijpers TW, Hoogerwerf M, van der Laan LJ, Nagel G, van der Schoot CE, Grunert F et al. (1992). CD66 nonspecific cross-reacting antigens are involved in neutrophil adherence to cytokine-activated endothelial cells. J Cell Biol 118: 457–466.

    Article  CAS  PubMed  Google Scholar 

  • Massague J, Chen YG . (2000). Controlling TGF-β signaling. Genes Dev 14: 627–644.

    CAS  PubMed  Google Scholar 

  • Myeroff LL, Parsons R, Kim S-J, Hedrick L, Cho KR, Orth K et al. (1995). A transforming growth factor β receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 55: 5545–5547.

    CAS  PubMed  Google Scholar 

  • Neumaier M, Paululat S, Chan A, Matthaes P, Wagener C . (1993). Biliary glycoprotein, a potential human cell adhesion molecule, is down-regulated in colorectal carcinomas. Proc Natl Acad Sci USA 90: 10744–10748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ordonez C, Screaton RA, Ilantzis C, Stanners CP . (2000). Human carcinoembryonic antigen functions as a general inhibitor of anoikis. Cancer Res 60: 3419–3424.

    CAS  PubMed  Google Scholar 

  • Park JG, Yang HK, Kim WH, Chung JK, Kang MS, Lee JH et al. (1997). Establishment and characterization of human gastric carcinoma cell lines. Int J Cancer 70: 443–449.

    Article  CAS  PubMed  Google Scholar 

  • Park K, Kim S-J, Bang Y-J, Park J-G, Kim NK, Roberts AB et al. (1994). Genetic changes in the transforming growth factor β (TGF-β) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-β. Proc Natl Acad Sci USA 91: 8772–8776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Screaton RA, DeMarte L, Draber P, Stanners CP . (2000). The specificity for the differentiation blocking activity of carcinoembryonic antigen resides in its glycophosphatidyl-inositol anchor. J Cell Biol 150: 613–626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wakefield LM, Roberts AB . (2002). TGF-β signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12: 22–29.

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H et al. (1999). Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J 18: 1280–1291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B et al. (1998). Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1: 611–617.

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann W . (1998). The nature and expression of the rodent CEA families: evolutionary considerations. In: Stanners CP (ed). Cell Adhesion and Communication Mediated by the CEA Family. Harwood Academic Publishers: Amsterdam, The Netherlands. pp 31–55.

    Google Scholar 

Download references

Acknowledgements

This work was supported by funds from the intramural program of National Cancer Institute. We thank Drs CP Stanners, J Massague, J Park, K Miyazono and S Kern for reagents, Dr A Roberts and Ms A Hobbie for the critical reading of the paper and M Anzano for Smad3 null mice.

Author information

Author notes

  1. S-U Han

    Present address: 6Current address: Department of Surgery, Ajou University School of Medicine, Suwon 442-721, Korea.,

  2. K H Her

    Present address: 7Current address: Department of Surgery, Cheju National University College of Medicine, Cheju 690-756, Korea.,

  3. Y-H Cho

    Present address: 8Current address: Division of Hematooncology, Department of Internal Medicine, KonKuk University Hospital, Seoul 143-729, Korea.,

  4. S-U Han and T-H Kwak: These two authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    S-U Han, T-H Kwak, K H Her, Y-H Cho, C Choi, H-J Lee, S Hong, Y S Park, T-A Kim & S-J Kim

  2. Division of Molecular Therapeutics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea

    H-J Lee

  3. Department of Biochemistry, Hanyang University College of Medicine, Seoul, Korea

    Y-S Kim

  4. Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea

    S-J Kim

Authors
  1. S-U Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T-H Kwak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K H Her
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y-H Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H-J Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y S Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y-S Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T-A Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S-J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S-J Kim.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Han, SU., Kwak, TH., Her, K. et al. CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling. Oncogene 27, 675–683 (2008). https://doi.org/10.1038/sj.onc.1210686

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210686

Keywords

This article is cited by

Search

Advanced search

Quick links