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Carcinogenesis, Vol. 24, No. 1, 25-29, January 2003
© 2003 Oxford University Press

CANCER BIOLOGY

Hypermethylation of metallothionein-3 CpG island in gastric carcinoma

Dajun Deng1,3, Wa'el El-Rifai2, Jiafu Ji1, Budong Zhu1, Paul Trampont2, Jiyou Li1, Michael F. Smith2 and Steven M. Powel2,3

1 Peking University Health Science Center and Beijing Institute for Cancer Research, Beijing, 100034, China and
2 Division of Gastroenterology and Hepatology, University of Virginia Health Systems, Charlottesville, VA 22908-0708, USA

The expression of metallothionein (MT)-3 is often markedly reduced in gastric carcinoma (GC). The molecular mechanism of this MT-3 downregulation is unknown. Transcriptional silencing of MT-3 by methylation of CpG island was investigated by nucleotide sequencing and denaturing high performance liquid chromatography (DHPLC) analyses. We found that normal brain tissue and a xenografted GC that expressed MT-3 mRNA had unmethylated regions of the CpG island in intron1 of this gene. On the other hand, gastric cancer cell lines AGS and MKN445, a xenografted GC, and a representative primary gastric cancer that had no expression of MT-3 mRNA demonstrated hypermethylation of the MT-3 intron1 CpG island. Treatment of the gastric cancer cell lines with 5-azacytidine resulted in new expression of MT-3 mRNA in these cells. A quantifying DHPLC assay was developed to determine the methylation status of this specific region of the MT-3 gene.

Fifty-eight primary GC and their corresponding normal gastric epithelial tissues, and 34 normal gastric mucosa were analyzed for MT-3 methylation by DHPLC in the region of methylation abnormalities initially identified. Our DHPLC analyses of the methylated MT-3 product demonstrated that the primary gastric cancers have an average methylation percentage of 6.3% per tumor compared with 2.4% in normal gastric tissues (P < 0.05). The MT-3 was not methylated in all of eight P53-positive GCs and hypermethylated in eight of 13 P53-negative cases by immunohistochemistry staining (P = 0.007). In conclusion, the CpG island in the MT-3 intron1 are abnormally hypermethylated in many gastric carcinomas and may account for the downregulation of MT-3 in gastric carcinogenesis.


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