Methylation and intratumoural heterogeneity of 14-3-3 sigma in oral cancer.
Methylation and intratumoural heterogeneity of 14-3-3 sigma in oral cancer.
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口腔癌中 14-3-3 σ 的甲基化和肿瘤内异质性。
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发表时间：
2007
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通讯作者：
H. Kuniyasu
中科院分区：
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作者：
U. Bhawal;K. Tsukinoki;T. Sasahira;F. Sato;Yusuke Mori;N. Muto;M. Sugiyama;H. Kuniyasu
14-3-3 sigma是一个主要的G2/M检查点控制基因，已证明其在多种癌症中的失活主要是通过表观遗传的超甲基化，而不是通过基因改变。本研究采用甲基化特异性聚合酶链式反应、逆转录聚合酶链式反应、Western blotting和免疫组织化学方法检测了46例口腔鳞癌组织中14-3-3sigma基因的甲基化状态和表达情况。用测序方法检测p53基因外显子的突变情况，用免疫组织化学方法检测细胞周期蛋白D1的突变情况。13%(6/46)的口腔肿瘤组织中存在14-3-3sigma基因甲基化，而相应的癌旁组织和正常牙周组织中均未检测到该基因甲基化。在肿瘤组织中发现了肿瘤内的异质性，包括三个14-3-3西格玛甲基化的样本。3例有P53突变的鳞癌和3例野生型P53的SCC中检测到14-3-3西格玛甲基化。我们的主要发现是：(A)14-3-3基因启动子甲基化在口腔癌中是一种罕见的事件；(B)它并不总是与14-3-3蛋白水平相关，它的甲基化与p53突变之间没有明显的关系；(C)14-3-3 sigma表达的缺失与细胞周期蛋白D1基因表达的降低有关。
14-3-3 sigma has been a major G2/M checkpoint control gene and has demonstrated that its inactivation in various cancers occurs mostly by epigenetic hypermethylation, not by genetic change. This study investigated the methylation status and expression of the 14-3-3 sigma gene in 46 oral squamous cell carcinomas by methylation-specific polymerase chain reaction, reverse transcriptase-polymerase chain reaction, Western blotting and immunohistochemistry. Exons of the p53 gene were examined for mutations by sequencing analysis and CyclinD1 by immunohistochemistry. Methylation of the 14-3-3 sigma gene was detected in 13% (6/46) of the oral tumours, but not in corresponding adjacent non-malignant and normal gingival tissues. Intratumoural heterogeneity was found in the tumour tissues including three 14-3-3 sigma-methylated samples. Methylation of 14-3-3 sigma was detected in 3 SCC with p53 mutations and 3 with wild-type p53. Our major findings are: (a) methylation of 14-3-3 gene promoter is a rare event in oral cancer; (b) it is not always associated with 14-3-3 protein levels and there is no clear relationship between its methylation and p53 mutation; (c) loss of 14-3-3 sigma expression is associated with reduced CyclinD1 gene expression.