Exclusive Association of p53 Mutation with Super-High Methylation of Tumor Suppressor Genes in the p53 Pathway in a Unique Gastric Cancer Phenotype.
Exclusive Association of p53 Mutation with Super-High Methylation of Tumor Suppressor Genes in the p53 Pathway in a Unique Gastric Cancer Phenotype.
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DOI：
10.1371/journal.pone.0139902
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Watanabe M
中科院分区：
文献类型：
--
作者：
Waraya M;Yamashita K;Ema A;Katada N;Kikuchi S;Watanabe M
对DNA甲基化基因的全面搜索确定了已被证明参与p53途径的凋亡过程的候选肿瘤抑制基因。在这项研究中，我们调查了p53突变与原发性胃癌的表观遗传学改变。检测了163例原发性胃癌中PGP9.5、NMDAR 2B和CCNA 1 3个基因的甲基化情况，这3个基因与p53肿瘤抑制通路相关，并与p53突变相结合。根据肿瘤p53突变状态评估表观遗传逆转与化疗药物组合对细胞凋亡的影响。 p53基因突变44例（27%），仅在野生型p53中发现3种基因的超高甲基化。男性（p = 0.003）、肠型（p = 0.005）和非浸润型（p = 0.001）的p53通路畸变率较高。p53通路畸变组在淋巴结、远端器官和腹膜中的复发率低于p53非畸变组。在NUGC 4胃癌细胞系（p53野生型）中，表观遗传治疗增加了化疗药物的凋亡，部分通过p53转录活性。另一方面，在KATO III癌细胞系（p53突变体）中，单独的表观遗传处理诱导了强烈的细胞凋亡，而没有p53的反式激活。在胃癌中，存在p53相关和非相关通路，并且具有任一通路类型的肿瘤表现出独特的临床特征。表观遗传学治疗可以部分通过p53激活诱导细胞凋亡，但其凋亡效应可能在很大程度上由p53途径以外的机制来解释。
A comprehensive search for DNA methylated genes identified candidate tumor suppressor genes that have been proven to be involved in the apoptotic process of the p53 pathway. In this study, we investigated p53 mutation in relation to such epigenetic alteration in primary gastric cancer. The methylation profiles of the 3 genes: PGP9.5, NMDAR2B, and CCNA1, which are involved in the p53 tumor suppressor pathway in combination with p53 mutation were examined in 163 primary gastric cancers. The effect of epigenetic reversion in combination with chemotherapeutic drugs on apoptosis was also assessed according to the tumor p53 mutation status. p53 gene mutations were found in 44 primary gastric tumors (27%), and super-high methylation of any of the 3 genes was only found in cases with wild type p53. Higher p53 pathway aberration was found in cases with male gender (p = 0.003), intestinal type (p = 0.005), and non-infiltrating type (p = 0.001). The p53 pathway aberration group exhibited less recurrence in lymph nodes, distant organs, and peritoneum than the p53 non-aberration group. In the NUGC4 gastric cancer cell line (p53 wild type), epigenetic treatment augmented apoptosis by chemotherapeutic drugs, partially through p53 transcription activity. On the other hand, in the KATO III cancer cell line (p53 mutant), epigenetic treatment alone induced robust apoptosis, with no trans-activation of p53. In gastric cancer, p53 relevant and non-relevant pathways exist, and tumors with either pathway type exhibited unique clinical features. Epigenetic treatments can induce apoptosis partially through p53 activation, however their apoptotic effects may be explained largely by mechanism other than through p53 pathways.