Abstract
DNA methylation has an important role in the development of carcinomas. As a metastasis suppressor gene, Raf kinase inhibitory protein (RKIP) suppresses tumor cell invasion and metastasis. In the present study, the associations between RKIP protein expression and promoter methylation with clinicopathological parameters, prognosis and survival rates in gastric adenocarcinoma were investigated. RKIP protein expression and promoter methylation were measured in 135 cases of surgically resected gastric adenocarcinoma specimens and corresponding normal tissues using immunohistochemistry and methylation-specific polymerase chain reaction, respectively. Kaplan-Meier analyses were performed to analyze the patient survival rate. Prognostic factors were determined using multivariate Cox analysis. RKIP promoter methylation was detected in 48.9% of gastric carcinoma tissues and 5.17% of adjacent tissues (P<0.05). RKIP protein expression was detected in 43.0% of gastric carcinoma tissues and 91.1% of adjacent tissues (P<0.05). The protein expression levels and promoter methylation of RKIP were shown to correlate with pathological staging, Union for International Cancer Control-stage, tumor differentiation and lymph node metastasis (P<0.05). In addition, the protein expression of RKIP in gastric carcinomas was demonstrated to be associated with promoter methylation of RKIP. Survival analysis of gastric carcinoma patients revealed that promoter methylation in RKIP-positive tumors correlated with a significantly shorter survival time when compared with RKIP-negative tumors (P=0.0002, using the log-rank test). Using multivariate Cox analysis, promoter methylation of RKIP was shown to be an independent prognostic factor (P=0.033). These results indicated that abnormal promoter methylation of RKIP may be one cause of downregulated RKIP expression. Downregulation of RKIP expression was shown to correlate with the incidence and development of gastric carcinomas. Thus, abnormal promoter methylation of RKIP may be a valuable biomarker for estimating gastric carcinoma prognosis.
Highlights
The development of gastric carcinoma is associated with the abnormal expression of multiple genes [1,2,3], and mechanisms of abnormal gene expression include genetic alterations and epigenetic changes [4]
Using multivariate Cox analysis, promoter methylation of Raf kinase inhibitory protein (RKIP) was shown to be an independent prognostic factor (P=0.033). These results indicated that abnormal promoter methylation of RKIP may be one cause of downregulated RKIP expression
Using the Methylation‐specific PCR (MSP) method and immunohistochemical staining, RKIP promoter methylation and expression were detected in 135 pairs of gastric adenocarcinoma tissues and their matched adjacent tissues
Summary
The development of gastric carcinoma is associated with the abnormal expression of multiple genes [1,2,3], and mechanisms of abnormal gene expression include genetic alterations and epigenetic changes [4]. Downregulation of RKIP expression has been observed in a number of types of human cancer, including breast carcinoma [12], acute myeloid leukemia [13], colorectal carcinoma [14] and melanomas [15]. These observations revealed that the expression of RKIP is lower in metastatic tissue compared with nonmetastatic tissue and correlated with decreased survival times, indicating that RKIP may be a prognostic marker of human cancer [16,17,18]. Guo et al [19] demonstrated that
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