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DIVERSITY OF CANCER CELLS CAUSED BY CYTOSINE METHYLATION IN NON-CPG ISLAND

非 CPG 岛中胞嘧啶甲基化引起的癌细胞多样性

基本信息

批准号：
16590278
负责人：
KITAZAWA Sohei
金额：
$ 2.18万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590278/
关键词：
Non CpG-island Methylation Gene promoter Bladder cancer BAMBI Gene transcription Pancreatic cancer TrkA メチル化 Desmoid tumor 神経周囲浸潤

项目摘要

Although global methylation at CpG islands leads to gene silencing, specific methylation at non-CpG islands would play a crucial epigenetic role in the versatility and plasticity of gene expression during cancer progression. We demonstrated the negative cis-acting AP-1-like sequence TGAGCGA in the 5'-untranslated region of the TrkA gene. Steady-state TrkA expression correlated positively with the accumulation of methylated CpG around the AP-1-like site. By EMSA, the AP-1-like site was bound mainly by c-Jun homodimers; the binding was blocked by Sss I-induced methylation. Consequently, activation of TrkA gene expression by methylation was caused by the direct interference of c-Jun binding to the negatively regulating AP-1-like site. Furthermore, methylated CpG around the AP-1-like site was accumulated with increased TrkA expression in cases of advanced pancreatic cancer with extensive perineural invasion.A rare case of desmoid-type fibromatosis with metaplastic ossification in the chest wall is analyzed. Accumulation of beta-catenin associated with a somatic activating mutation in codon 41 was demonstrated. Bisulfite mapping using microdissected samples showed that BMP and activin membrane-bound inhibitor (BAMBI) expression was specifically downregulated at the ossifying focus due to hypermethylation of its gene promoter. Because both BMP and classical Wnt/beta-catenin/LEF1 signaling cooperatively and mutually induce differentiation of mesenchymal cells into osteoblastic cells and promote bone formation, the epigenetic event leading to the enhanced responsiveness to BMP signaling may play a crucial role in the formation of metaplastic bone.We have presented our data at various international as well as domestic meetings, and published scientific papers for academic journals.

虽然CpG岛上的整体甲基化导致基因沉默，但非CpG岛上的特异性甲基化在癌症进展过程中基因表达的多功能性和可塑性中发挥着关键的表观遗传学作用。我们在TrkA基因的5‘非翻译区发现了负顺式作用的AP-1样序列TGAGCGA。TrkA的稳定表达与AP-1样位点周围甲基化CpG的积聚呈正相关。在EMSA中，AP-1样位点主要与c-jun同源二聚体结合，这种结合被Sss I诱导的甲基化所阻断。因此，TrkA基因的甲基化激活是由于c-jun结合到负调控的AP-1样位点的直接干扰所致。此外，在伴有广泛神经侵袭的晚期胰腺癌中，AP-1样位点周围的甲基化CpG随着TrkA表达的增加而积聚。本文分析了一例罕见的韧带样型纤维瘤病胸壁化生骨化。在密码子41中发现了与体细胞激活突变相关的β-连环蛋白的积累。显微解剖标本的亚硫酸氢盐定位结果表明，BMP和激活素膜结合抑制物(BAMBI)基因启动子的高甲基化导致BMP和激活素膜结合抑制物(BAMBI)在骨化灶的表达特异性下调。由于BMP和经典的Wnt/β-catenin/LEF1信号相互协同地诱导间充质细胞分化为成骨细胞并促进骨形成，导致对BMP信号反应增强的表观遗传事件可能在化生骨的形成中起关键作用。我们在各种国际和国内会议上发表了我们的数据，并在学术期刊上发表了科学论文。