Decreased expression and aberrant methylation of Gadd45G is associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma
Decreased expression and aberrant methylation of Gadd45G is associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma
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Gadd45G 表达降低和异常甲基化与食管鳞状细胞癌的肿瘤进展和不良预后相关
DOI：
10.1007/s10585-013-9597-2
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发表时间：
2013-12-01
影响因子：
4
通讯作者：
Kuang, Gang
中科院分区：
文献类型：
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作者：
Guo, Wei;Zhu, Tienian;Kuang, Gang
生长停滞DNA损伤诱导基因（growth arrest DNA damage-inducible gene，Gadd 45）家族由Gadd 45 A、Gadd 45 B和Gadd 45 G组成，参与DNA损伤反应和细胞生长停滞。本研究旨在检测Gadd 45基因家族在食管癌中的作用以及Gadd 45 G甲基化与食管鳞状细胞癌（ESCC）一系列病理参数的关系，以期进一步阐明Gadd 45基因家族在ESCC发病机制中的作用。在食管癌细胞系中发现Gadd 45 G频繁沉默，但Gadd 45 A和Gadd 45 B没有沉默，并且5-Aza-dC或TSA处理Eca 109细胞系可以逆转Gadd 45 G的沉默。Eca 109细胞中Gadd 45 G近端启动子异常甲基化诱导Gadd 45 G表达沉默Gadd 45 A mRNA和蛋白在食管鳞癌组织中的表达与相应正常组织相比有显著性差异。食管鳞癌组织中Gadd 45 G基因mRNA和蛋白表达均降低，且与Gadd 45 G近端启动子甲基化有关。Gadd 45 A或Gadd 45 B表达与ESCC患者生存无关，而Gadd 45 G甲基化状态和蛋白表达与ESCC患者生存独立相关。提示Gadd 45 G可能是一种功能性抑癌基因，其近端甲基化失活可能在ESCC的发生中起重要作用，Gadd 45 G基因的重新激活可能具有治疗潜力，并可作为ESCC患者预后的标志物。
The growth arrest DNA damage-inducible gene (Gadd45) family, which is composed of Gadd45A, Gadd45B, and Gadd45G, is involved in DNA damage response and cell growth arrest. The present study was to detect the role of Gadd45 gene family in esophageal cancer and the relationship of Gadd45G methylation to a series of pathological parameters in a large esophageal squamous cell carcinoma (ESCC) sample, in order to elucidate more information on the role of Gadd45 gene family with regard to the pathogenesis of ESCC. Frequent silencing of Gadd45G but not Gadd45A and Gadd45B were found in esophageal cancer cell lines and the silencing of Gadd45G may be reversed by 5-Aza-dC or TSA treatment in Eca109 cell line. The aberrant proximal promoter methylation of Gadd45G induces silencing of Gadd45G expression in Eca109 cell line. Gadd45A mRNA and protein expression in ESCC tumor tissues was significantly different compared to corresponding normal tissues. Decreased mRNA and protein expression of Gadd45G was observed in ESCC tumor tissues and was associated with Gadd45G proximal promoter methylation. Gadd45A or Gadd45B expression was not correlated with ESCC patients survival, while Gadd45G methylation status and protein expression were independently associated with ESCC patients’ survival. These data indicated that Gadd45G may be a functional tumor suppressor and its inactivation through proximal promoter methylation may play an important role in ESCC carcinogenesis and reactivation of Gadd45G gene may has therapeutic potential and may be used as a prognostic marker for ESCC patients.