Promoter hypermethylation and inactivation of O6-methylguanine-DNA methyltransferase in esophageal squamous cell carcinomas and its reactivation in cell lines

作者：Mingzhu Fang, Zhe Hu Jin, Yimin Wang, Jie Liao, Guang‐Yu Yang, Lidong Wang, Chung Shu Yang · 发表于：International Journal of Oncology · 年份：2005 · DOI：10.3892/ijo.26.3.615 · 被引用次数：76 · 研究领域：Epigenetics and DNA Methylation、Cancer-related gene regulation、Esophageal Cancer Research and Treatment

The purpose of this study was to characterize the role of DNA hypermethylation in the loss of expression of O(6)-methylguanine-DNA methyltransferase (MGMT) during the development of esophageal squamous cell carcinoma (ESCC) and to investigate its reactivation in cell lines. Samples were collected from Linzhou City of the Henan province in northern China, a high-risk area of this disease. The hypermethylation of promoter CpG islands of the MGMT gene was examined by methylation-specific PCR in ESCC and neighboring non-tumorous tissues, as well as in laser capture microdissected samples with normal epithelium, basal cell hyperplasia (BCH), and dysplasia (DYS). The MGMT mRNA and protein expression were determined with RT-PCR and immunohistochemistry, respectively. Five of 17 (29%) normal, 10 of 20 (50%) BCH, 8 of 12 (67%) DYS, and 13 of 18 (72%) ESCC samples had DNA hypermethylation in the MGMT promoter region, showing a gradual increase with the progression of carcinogenesis. The frequency of the loss of MGMT mRNA and protein expression progressively decreased from normal to BCH, DYS, and ESCC, and it was highly correlated with MGMT promoter hypermethylation according to Fisher's exact tests. When each individual sample was considered, good concordance between DNA hypermethylation and the loss of expression of MGMT was also observed. In samples from the same patient, if hypermethylation was detected in earlier lesions, it was usually observed in more severe lesions. In the ESCC ...