High frequency of promoter hypermethylation of metallothionein 1E in endometrial carcinomas

Abstract

Metallothioneins (MT) are a family of cysteine-rich, low-molecular-weight, metal-binding proteins consisting of ten functional isoforms in human. Their main functions have been associated with metal ion homeostasis, protection against oxidative damage, cell proliferation and apoptosis. Increased expression of MT was commonly found in various human tumors. However, expressions of different isoforms vary amongst tumors. The antiapoptotic MT-1E gene was found to be up-regulated in estrogen receptor-negative ductal breast cancer but largely unchanged in renal cell carcinoma. In contrast, in our own microarray analysis, MT-1E was found to be down-regulated in endometrial cancer cells as compared with normal endometrial cells. We further pursued analyzing the methylation status of the CG-rich promoter region of MT-1E using methylation-sensitive restriction enzymes, Hha I and Hpa II followed by PCR amplification. We found the occurrence of hypermethylation of the CpG islands within the promoter region of MT-1E. In a set of endometrial carcinomas, 42.4% (53/125) of the samples were hypermethylated, while none of the normal samples (0/38) was methylated. There was no correlation between the methylation status of MT-1E and clinico-pathological characteristics, including the stage and grade of the diseases, survival and disease-free interval. This is the first report describing the occurrence of promoter hypermethylation of MT-1E in human tumor. Based on the high frequency of occurrence, methylation of MT-1E may be developed as a new biomarker for endometrial cancer detection. Finally, in order to understand the biological significance of MT during tumor development and progression, detailed analysis of the expression of individual isoform and its functions in various human tumors is needed.