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Differential Expression of Methionine Adenosyltransferase Genes Influences the Rate of Growth of Human Hepatocellular Carcinoma Cells¹

Center for Liver Disease Research and Division of Gastrointestinal and Liver Diseases, Department of Medicine [J. C., Z. M., S. C. L.], and Gene Therapy Laboratories [J-J. H.], University of Southern California School of Medicine, Los Angeles, California 90033

Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine (SAM), the principal methyl donor, and is essential to normal cell function. The two forms of MAT, liver specific and non-liver specific, are products of two genes, MAT1A and MAT2A, respectively. We have reported a switch from MAT1A to MAT2A gene expression in human liver cancer cells. In the current work, we examined whether the type of MAT expressed by the cell influences cell growth. HuH-7 cells were stably transfected with MAT1A and were subsequently treated with antisense oligonucleotides directed against MAT2A. MAT2A antisense treatment reduced the amount of MAT2A mRNA by 99% but had no effect on MAT1A mRNA. Cell growth and DNA synthesis rates were reduced by 20–25% after transfection with MAT1A and by an additional 30–40% after MAT2A antisense treatment. SAM level and SAM:S-adenosylhomocysteine (SAH) ratio increased by 50–75% after MAT1A transfection and by an additional 60–80% after MAT2A antisense treatment. DNA methylation changed in parallel to changes in SAM level and SAM:SAH ratio. Supplementing untransfected HuH-7 cells with SAM in the culture medium increased SAM level, SAM:SAH ratio, and DNA methylation and decreased cell growth and DNA synthesis. In conclusion, cell growth is influenced by the type of MAT expressed. The mechanism likely involves changes in SAM:SAH ratio and DNA methylation.

¹ This work was supported by NIH Grant DK51719 and the Wright Foundation. The University of Southern California Center for Liver Disease Research is supported by NIH Grant DK48522.

² To whom requests for reprints should be addressed, at MUDD Room 410, Department of Medicine, USC School of Medicine, 1333 San Pablo Street, Los Angeles, CA, 90033. Phone: (213) 342-2441; Fax: (213) 342-3243; E-mail: shellylu@hsc.usc.edu.

Received 10/30/97. Accepted 1/23/98.

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