Aberrant methylation and loss expression of RKIP is associated with tumor progression and poor prognosis in gastric cardia adenocarcinoma
Aberrant methylation and loss expression of RKIP is associated with tumor progression and poor prognosis in gastric cardia adenocarcinoma
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DOI：
10.1007/s10585-012-9533-x
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发表时间：
2013-03-01
影响因子：
4
通讯作者：
Yang, Zhibin
中科院分区：
文献类型：
--
作者：
Guo, Wei;Dong, Zhiming;Yang, Zhibin
Raf 激酶抑制蛋白 (RKIP) 已被确定为一类新型分子的成员，该分子参与癌症进展并抑制肿瘤的转移扩散。本研究的目的是研究RKIP的启动子甲基化和表达，以确定RKIP在胃贲门腺癌（GCA）中的预后意义。分别采用MSP法和免疫组化法检测GCA组织中RKIP的甲基化状态和蛋白表达。 GCA肿瘤组织中RKIP甲基化频率（62.1%）显着高于相应正常组织（4.1%），且与TNM分期、组织学分化、浸润深度、LN转移、远处转移或复发以及上消化道癌（UGIC）家族史相关。 GCA肿瘤组织中RKIP的阳性染色（34.5%）显着低于相应的正常组织（84.1%），并且与RKIP甲基化相关。 RKIP 可能通过调节 Raf-1/MEK/ERK 信号通路在 GCA 中充当抑癌基因。 III期和IV期GCA患者，具有阳性UGIC家族史、RKIP高甲基化和下调表达，最有可能发生转移性疾病，且生存率也较差。使用多变量 Cox 回归分析，GCA 中的 RKIP 甲基化是生存的独立预后标志物 (P = 0.04)。总之，RKIP 的异常高甲基化可能是导致 GCA 基因表达缺失或下调的机制之一，尤其是在有 UGIC 家族史的个体中。此外，高甲基化和 RKIP 表达缺失可用作预测 GCA 临床结果的标志物。
Raf kinase inhibitory protein (RKIP) has been identified as a member of a novel class of molecules which implicated in cancer progression and suppress the metastatic spread of tumors. The aim of this study was to investigate the promoter methylation and expression of RKIP, determine the prognostic significance of RKIP in gastric cardia adenocarcinoma (GCA). MSP approach and immunohistochemistry methods were used respectively to examine methylation status and protein expression of RKIP in GCA tissues. The frequency of RKIP methylation in GCA tumor tissues (62.1 %) was significantly higher than that in corresponding normal tissues (4.1 %) and was associated with TNM stage, histological differentiation, depth of invasion, LN metastasis, distant metastasis or recurrence, and upper gastrointestinal cancers (UGIC) family history. Positive staining of RKIP in GCA tumor tissues (34.5 %) was significantly decreased than that in corresponding normal tissues (84.1 %) and was associated with RKIP methylation. RKIP may act as a tumor suppressor gene in GCA by regulation of the Raf-1/MEK/ERK signaling pathway. GCA patients in stage III and IV, with positive UGIC family history, and hypermethylation and down-expression of RKIP were most likely to develop metastatic disease and also showed the worse survival. RKIP methylation in GCA was an independent prognostic marker for survival using multivariate Cox regression analysis (P = 0.04). In all, aberrant hypermethylation of RKIP may be one of the mechanisms that lead to loss or down expression of the gene in GCA especially in individuals with UGIC family history. Additionally, hypermethylation and loss of RKIP expression may be used as a marker to predict clinical outcome of GCA.