Department of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankanglu 12, Shijiazhuang, 050011, Hebei, China.
Clin Exp Metastasis. 2013 Mar;30(3):265-75. doi: 10.1007/s10585-012-9533-x. Epub 2012 Sep 16.
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.
Raf 激酶抑制蛋白（RKIP）已被鉴定为一种新型分子的成员，该分子参与癌症的进展并抑制肿瘤的转移扩散。本研究旨在探讨 RKIP 的启动子甲基化和表达，确定 RKIP 在胃食管腺癌（GCA）中的预后意义。分别采用 MSP 方法和免疫组织化学方法检测 GCA 组织中 RKIP 的甲基化状态和蛋白表达。GCA 肿瘤组织中 RKIP 的甲基化频率（62.1%）明显高于相应的正常组织（4.1%），并与 TNM 分期、组织学分化、浸润深度、淋巴结转移、远处转移或复发以及上消化道癌症（UGIC）家族史有关。GCA 肿瘤组织中 RKIP 的阳性染色（34.5%）明显低于相应的正常组织（84.1%），并与 RKIP 甲基化有关。RKIP 可能通过调节 Raf-1/MEK/ERK 信号通路在 GCA 中发挥肿瘤抑制基因的作用。GCA 患者在 III 期和 IV 期、有阳性 UGIC 家族史、RKIP 高甲基化和低表达的患者最有可能发生转移疾病，且生存情况也较差。使用多变量 Cox 回归分析，RKIP 甲基化是 GCA 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 中基因缺失或低表达的机制之一，尤其是在有 UGIC 家族史的个体中。此外，RKIP 的高甲基化和表达缺失可用作预测 GCA 临床结局的标志物。
