Methylation of the ASC gene promoter is associated with aggressive prostate cancer
Methylation of the ASC gene promoter is associated with aggressive prostate cancer
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DOI：
10.1002/pros.20371
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发表时间：
2006-05-15
期刊：
影响因子：
2.8
通讯作者：
O'Keefe, DS
中科院分区：
文献类型：
--
作者：
Collard, RL;Harya, NS;O'Keefe, DS
背景。本研究的目的是调查前列腺癌细胞系和人体组织中含有 CARD（ASC；TMS1；PYCARD）的凋亡相关斑点样蛋白的甲基化状态，并确定这些发现是否与前列腺癌的临床病理特征相关。从前列腺细胞系和显微解剖组织中分离基因组 DNA，通过甲基化特异性聚合酶链式反应 (MSP) 进行亚硫酸氢盐转化和分析。通过定量或定性RT-PCR测定用或不用甲基化抑制剂处理的前列腺癌细胞系中ASC的表达。结果。在五种前列腺癌细胞系中，ASC 基因表达被沉默或减少，并与甲基化状态相关。用甲基化抑制剂 5-aza-2-deoxycitidine 和 Zebularine 处理 MDAPCa2b 前列腺癌细胞可重新激活 ASC 的表达。在 58 个前列腺癌样本中，ASC 启动子区域的甲基化存在于 65% 的原发癌组织、64% (7/11) 的癌症相关高级别前列腺上皮内瘤变 (HG-PIN) 以及 28% 的外观正常但邻近肿瘤前列腺组织中。虽然ASC甲基化与Gleason评分（P = 0.46）或病理分期（P = 0.75）无关，但生化复发患者的邻近正常组织中ASC甲基化频率显着较高（P = 0.0383）。结论。 ASC 基因启动子的甲基化是前列腺癌致癌过程中的常见且早期事件。令人惊讶的是，在后来经历生化复发的患者中，邻近正常组织的甲基化发生的频率明显更高，这表明 ASC 基因失活在侵袭性疾病的初始阶段发挥了作用。
BACKGROUND. The aim of this study was to investigate the methylation status of apoptosis-associated speck-like protein containing a CARD (ASC; TMS1; PYCARD) in prostate cancer cell lines and human tissues and to determine if those findings correlate with the clinicopathological features of prostate cancer.METHODS. Genomic DNA was isolated from prostate cell lines and microdissected tissues, bisulfite converted and analyzed by methylation specific polymerase chain reaction (MSP). Expression of ASC in prostate cancer cell lines treated with or without methylation inhibitors was determined by quantitative or qualitative RT-PCR.RESULTS. ASC gene expression was silenced or reduced in five prostate cancer cell lines and correlated with methylation status. Treatment of MDAPCa2b prostate cancer cells with the methylation inhibitors 5-aza-2-deoxycitidine and Zebularine reactivated expression of ASC. Of 58 prostate cancer specimens, methylation of the ASC promoter region was present in 65% of primary cancer tissue, 64% (7/11) of cancer-associated high grade-prostatic intraepithelial neoplasia (HG-PIN), and 28% of normal-appearing but adjacent to tumor prostate tissue. While ASC methylation was not related to Gleason score (P = 0.46) or pathological stage (P = 0.75), there was a significantly higher frequency of ASC methylation in the adjacent normal tissue for patients with biochemical recurrence (P = 0.0383).CONCLUSIONS. Methylation of the ASC gene promoter is both a frequent and early event in prostate cancer carcinogenesis. Surprisingly, methylation of the adjacent normal tissue occurs significantly more often in patients who later undergo biochemical recurrence, suggesting a role for inactivation of the ASC gene in the initial stages of aggressive disease.