Promoter hypomethylation up-regulates CD147 expression through increasing Sp1 binding and associates with poor prognosis in human hepatocellular carcinoma.
Promoter hypomethylation up-regulates CD147 expression through increasing Sp1 binding and associates with poor prognosis in human hepatocellular carcinoma.
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启动子低甲基化通过增加 Sp1 结合上调 CD147 表达，并与人肝细胞癌的不良预后相关。
DOI：
10.1111/j.1582-4934.2010.01124.x
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发表时间：
2011-06
影响因子：
5.3
通讯作者：
Chen ZN
中科院分区：
文献类型：
--
作者：
Kong LM;Liao CG;Chen L;Yang HS;Zhang SH;Zhang Z;Bian HJ;Xing JL;Chen ZN
CD 147是一种跨膜糖蛋白，在人肝细胞癌（HCC）中过表达，可促进HCC的进展和转移。启动子甲基化是基因调控中最重要的过程之一。本研究旨在探讨CD 147基因启动子甲基化状态与肝癌临床病理特征及预后的关系。应用亚硫酸氢盐基因组测序、甲基化特异性PCR、实时荧光定量RT-PCR、Western blot和免疫组化方法检测正常和肝癌细胞系以及54对肝癌和癌旁非肿瘤组织中CD 147启动子甲基化状态和表达水平。统计分析HCC患者CD 147基因启动子区甲基化状态与其表达水平及临床病理特征的关系。与正常细胞系和组织对照相比，在HCC细胞系中观察到显著更高的CD 147表达和显著更低的启动子甲基化水平。体内和体外分析表明，5-氮杂-2 ′-脱氧胞苷去甲基化通过增强Sp1结合亲和力导致CD 147表达增加，甲基转移酶甲基化通过干扰Sp1结合降低CD 147转录活性。CD 147基因启动子甲基化水平在HCC组织中为22.22%，在ANT组织中为46.30%，两组差异有统计学意义（P < 0.05）。在HCC组织中，CD 147表达与甲基化水平之间存在显著的负相关性（r=-0.615）。此外，CD 147启动子未甲基化的HCC患者的复发率（88.1%vs58.3%; P < 0.05）和死亡率（83.3%vs50.0%; P < 0.05）显著高于CD 147启动子甲基化的患者。总之，启动子低甲基化主要通过增加Sp1结合上调CD 147表达，并与HCC患者的不良预后相关。
CD147 is a transmembrane glycoprotein overexpressed in human hepatocellular carcinoma (HCC) which could promote HCC progression and metastasis. Promoter methylation is one of the most important processes in gene regulation. In this study, we aim to investigate CD147 promoter methylation status and the correlation with clinicopathological features and prognosis in HCC. CD147 promoter methylation statuses and expression levels in normal and HCC cell lines and 54 paired HCC and adjacent non-tumour (ANT) tissues were, respectively, examined by bisulphite genomic sequencing, methylation-specific PCR, real-time RT-PCR, Western blot and immunohistochemistry. The correlations of promoter methylation statuses with CD147 expression level and the clinicopathological features were statistically analysed in HCC patients. Significantly higher expression of CD147 and significantly lower promoter methylation level were observed in HCC cell lines compared to normal cell lines and tissues control. In vivo and in vitro analysis indicated that demethylation with 5-Aza-2′-deoxycytidine led to increased CD147 expression through enhancing Sp1 binding affinity, and methylation with methyltransferase reduced CD147 transcriptional activity through interfering Sp1 binding. CD147 promoter methylation level in HCC tissues (22.22%) was lower than that in ANT tissues (46.30%; P < 0.05). Within HCC tissues, a significant inverse correlation was observed between CD147 expression and methylation level (r=−0.615). Moreover, HCC patients with unmethylated CD147 promoter had a significantly higher recurrence rate (88.1%versus 58.3%; P < 0.05) and death rate (83.3%versus 50.0%; P < 0.05) than patients with methylated CD147 promoter. In conclusions, promoter hypomethylation up-regulates CD147 expression primarily through increasing Sp1 binding and associates with poor prognosis in HCC patients.
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影响因子：
6.4
作者：
Li, Yu;Xu, Jing;Chen, Zhi-Nan
通讯作者：
Chen, Zhi-Nan
影响因子：
29.4
作者：
Liedtke, C;Zschemisch, NH;Trautwein, C
通讯作者：
Trautwein, C
影响因子：
3.5
作者：
Koga, T;Suico, MA;Kai, H
通讯作者：
Kai, H
囊性纤维化上皮细胞中 Toll 样受体 2 基因表达的 DNA 去甲基化依赖性增强涉及 SP1 激活的转录。
影响因子：
--
作者：
Furuta, Takashi;Shuto, Tsuyoshi;Shimasaki, Shogo;Ohira, Yuko;Suico, Mary Ann;Gruenert, Dieter C.;Kai, Hirofumi
通讯作者：
Kai, Hirofumi
影响因子：
1.5
作者：
KANEKURA, T;MIYAUCHI, T;MURAMATSU, T
通讯作者：
MURAMATSU, T