1. ¹Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2. ²Division of Molecular Therapeutics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
3. ³Department of Biochemistry, Hanyang University College of Medicine, Seoul, Korea
4. ⁴Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea

Correspondence: Dr S-J Kim, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Building 37, Room 5046D, 9000 Rockville Pike, Bethesda, MD 20892, USA. E-mail: kims@mail.nih.gov or jasonsjkim@gachon.ac.kr

⁵These two authors contributed equally to this work.

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

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

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

Received 28 August 2006; Revised 29 May 2007; Accepted 16 June 2007; Published online 23 July 2007.

Abstract

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