Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer
Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer
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DOI：
10.1097/mpa.0b013e3181630ffe
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发表时间：
2008-05-01
期刊：
影响因子：
2.9
通讯作者：
Malafa, Mokenge P.
中科院分区：
文献类型：
--
作者：
Park, Jong Y.;Helm, James F.;Malafa, Mokenge P.
目的：在胰腺癌中已经确定了很少的基因突变，而导致基因沉默的表观遗传变化在几个基因中是已知的。由于SLC5A8被认为是一种潜在的肿瘤抑制基因，在其他几种癌症中被表观遗传学变化下调，我们试图描述胰腺癌中启动子甲基化状态及其与SLC5A8表达的关系。方法：采用甲基化特异性引物，检测胰腺癌细胞系、肿瘤和胰腺癌患者邻近非肿瘤组织中SLC5A8的启动子甲基化和表达。结果：所有肿瘤组织中均检测到SLC 5A8表达的完全或部分缺失。对不表达SLC5A8的胰腺癌细胞系的亚硫酸氢盐测序分析检测到启动子区域的密集甲基化。SLC5A8的表达通过氮杂脱氧胞苷或阿司他丁A处理而重新激活。甲基化特异性聚合酶链反应检测10例胰腺癌组织中有7例发生甲基化，而28例癌旁组织中仅3例发生甲基化（P < 0.001）。我们认为，SLC5A8可能作为一个肿瘤抑制基因，其沉默的表观遗传变化可能有助于胰腺癌的发生和发展。
Objectives: Few genetic mutations have been identified in pancreatic adenocarcinoma, whereas epigenetic changes that lead to gene silencing are known in several genes. Because SLC5A8 is regarded as a potential tumor suppressor gene that is down-regulated by epigenetic changes in several other cancers, we sought to characterize promoter methylation status and its relationship to SLC5A8 expression in pancreatic cancer. .Methods: Promoter methylation and expression of SLC5A8 were evaluated in pancreatic cancer cell lines, tumor, and adjacent nontumor tissues from pancreatic cancer patients using methylationspeci. c polymerase chain reaction analysis, quantitative real-time and semiquantitative reverse transcriptaseYpolymerase chain reaction, and bisulfate-modi edsequencing.Results: Complete or partial loss of SLC5A8 expression was observed in all tumor tissues. Bisulfte sequencing analysis on pancreatic cancer cell lines that did not express SLC5A8 detected dense methylation of the promoter region. SLC5A8 expression was reactivated by treatment with aza-deoxycytidine or trichostatin A. Methylation-specific polymerase chain reaction detected methylation in 7 of 10 pancreatic tumor tissues, whereas in only 3 of 28 adjacent nontumor tissues (P < 0.001).Conclusions: Our findings indicate loss of SLC5A8 expression as a result of aberrant promoter methylation in pancreatic adenocarcinoma. We suggest that SLC5A8 may function as a tumor suppressor gene whose silencing by epigenetic changes may contribute to carcinogenesis and progression of pancreatic cancer.