MT1G hypermethylation is associated with higher tumor stage in prostate cancer
MT1G hypermethylation is associated with higher tumor stage in prostate cancer
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DOI：
10.1158/1055-9965.epi-04-0659
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发表时间：
2005-05-01
影响因子：
3.8
通讯作者：
Sidransky, D
中科院分区：
文献类型：
--
作者：
Henrique, R;Jerónimo, C;Sidransky, D
目的：锌参与多种生理过程，包括细胞生长和增殖。虽然在正常的前列腺组织中锌含量很高，但在前列腺癌中却明显降低。金属硫蛋白控制锌的生物利用度，其中一种异构体MT1G在前列腺癌中被报道下调。在这里，我们研究了启动子甲基化是否可能导致前列腺癌中MT1G沉默。患者和方法：采用定量甲基化特异性PCR对前瞻性收集的121例前列腺癌患者、39例配对的高级别前列腺上皮内瘤变（HGPIN）、29例良性前列腺增生患者、13例膀胱前列腺切除术标本中正常前列腺组织样本和前列腺癌细胞系的组织样本进行MT1G启动子检测。计算甲基化水平，并与临床和病理变量相关。在细胞系中进行逆转录- pcr以评估去甲基化处理前后MT1G mRNA的表达。结果121例前列腺癌中29例、39例HGPIN中5例、29例良性前列腺增生中3例、13例正常前列腺组织中0例出现MT1G启动子超甲基化。在甲基化频率或水平上没有发现显著差异（P = 0.057）。甲基化水平与肿瘤分期相关，但与Gleason分级无关。MT1G超甲基化在前列腺癌中扩散到前列腺外更常见。所有前列腺癌细胞系均显示MT1G启动子甲基化，但去甲基化后表达无明显差异。结论：我们的研究结果表明，MT1G启动子甲基化与前列腺癌的肿瘤侵袭性有关，可能是局部晚期疾病的标志。
Purpose: Zinc is involved in several physiologic processes, including cell growth and proliferation. Although in normal prostate tissue zinc levels are high, there is a marked decrease in prostate cancer. Metallothioneins control the bioavailability of zinc and one isoform, MT1G, was reported down-regulated in prostate cancer. Here, we investigated whether promoter methylation might cause MT1G silencing in prostate cancer.Patients and Methods: The MT1G promoter was assessed by quantitative methylation-specific PCR on prospectively collected tissue samples from 121 patients with prostate cancer, 39 paired high-grade prostatic intraepithelial neoplasias (HGPIN), 29 patients with benign prostatic hyperplasia, 13 normal prostate tissue samples from cystoprostatectomy specimens, and prostate cancer cell lines. The methylation levels were calculated and were correlated with clinical and pathologic variables. Reverse transcription-PCR was done in cell lines to assess MT1G mRNA expression before and after demethylating treatment.Results: MT1G promoter hypermethylation was found in 29 of 121 prostate cancer, 5 of 39 HGPIN, 3 of 29 benign prostatic hyperplasia, and 0 of 13 normal prostate tissue samples. No significant differences in methylation frequencies or levels were found (P = 0.057, for both). Methylation levels were found to correlate with tumor stage but not with Gleason grade. MT1G hypermethylation was more frequent in prostate cancer that spread beyond the prostate capsule. All prostate cancer cell lines tested showed MT1G promoter methylation, but no differences in expression were apparent after demethylation.Conclusions: Our findings suggest that MT1G promoter methylation is associated with tumor aggressiveness in prostate cancer and it might be a marker of locally advanced disease.