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Correlation of DNA Hypomethylation with Expression of carcinoembryonic Antigen in Human Colon Carcinoma Cells¹

Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892 [R. T., S. V. S. K., J. K., J. W. G., J. S.]; the Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 [S. P.]; and the Divisions of Immunology and Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010 [J. E. S.]

Using an assay based on the binding of a carcinoembryonic antigen (CEA)-specific monoclonal antibody, we have examined the expression of carcinoembryonic antigen genes in human colon tumor and normal fibroblast cell lines. CEA expression was not detectable in the normal fibroblast cell lines, whereas varying levels of high CEA expression were found in the colon tumor cell lines LS-174T, GEO, and WIDR. We have used a 550-base pair CEA probe derived from cloned complementary DNA to carry out Southern analysis of the DNA isolated from the normal and colon tumor cell lines. At high stringency, the CEA probe detected seven BamHI fragments in all DNAs analyzed. At low stringency, however, 14 BamHI fragments ranging from 1.5 to 23 kilobases were detected. Results of the Southern analysis demonstrate no amplification or rearrangement of the CEA genes in tumor cells. We used methylation-sensitive restriction endonucleases, HpaII and HhaI, to compare the degree of methylation of CEA family of genes in normal and colon tumor cell lines. Our results demonstrate that the CEA family of genes exists in a state of hypermethylation in the normal cell lines. In contrast, the CEA gene(s) are relatively hypomethylated in the tumor cell lines, suggesting a correlation between the state of methylation and degree of expression of the CEA gene(s). A comparison of the state of methylation of the CEA gene(s) in cells before and after treatment with the -interferon (which up-regulates CEA steady-state mRNA levels) showed no detectable difference in the degree of DNA methylation. The segments of CEA genes that are hypermethylated in normal cells, but are hypomethylated in tumor cells, were also identified. Thus, these studies may help identify the sites of methylation that are crucial for the control of CEA gene regulation.

¹ This study was supported in part by National Cancer Institute Grant CA37808 to John E. Shively.

² Present address: Department of Immunology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.

³ To whom requests for reprints should be addressed, at Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bldg. 10, Room 8B07, Bethesda, MD 20892.

Received 4/ 5/88. Revised 7/13/88. Accepted 7/18/88.

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