Promoter methylation of Raf kinase inhibitory protein: A significant prognostic indicator for patients with gastric adenocarcinoma

Li,Dong‑Xia; Cai,Hai‑Yang; Wang,Xia; Feng,Yan‑Ling; Cai,Song‑Wang

doi:10.3892/etm.2014.1833

Promoter methylation of Raf kinase inhibitory protein: A significant prognostic indicator for patients with gastric adenocarcinoma

Authors:
- Dong‑Xia Li
- Hai‑Yang Cai
- Xia Wang
- Yan‑Ling Feng
- Song‑Wang Cai
View Affiliations

Affiliations: School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China, Department of Pathology, Public Health Clinical Center of Fudan University, Shanghai 201508, P.R. China, Department of Cardiothoracic Surgery, Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
Published online on: July 8, 2014 https://doi.org/10.3892/etm.2014.1833
Pages: 844-850

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Begnami MD, Fukuda E, Fregnani JH, et al: Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 29:3030–3036. 2011. View Article : Google Scholar : PubMed/NCBI
2	Zhang L, Xu Z, Xu X, et al: SALL4, a novel marker for human gastric carcinogenesis and metastasis. Oncogene. Nov 25–2013.(Epub ahead of print).
3	Tang H, Deng M, Tang Y, et al: miR-200b and miR-200c as prognostic factors and mediators of gastric cancer cell progression. Clin Cancer Res. 19:5602–5612. 2013. View Article : Google Scholar : PubMed/NCBI
4	You JS and Jones PA: Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell. 22:9–20. 2012. View Article : Google Scholar : PubMed/NCBI
5	Baylin SB and Jones PA: A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 11:726–734. 2011. View Article : Google Scholar : PubMed/NCBI
6	Taby R and Issa JP: Cancer epigenetics. CA Cancer J Clin. 60:376–392. 2010. View Article : Google Scholar
7	Hu X, Sui X, Li L, et al: Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol. 229:62–73. 2013. View Article : Google Scholar : PubMed/NCBI
8	Yu J, Liang QY, Wang J, et al: Zinc-finger protein 331, a novel putative tumor suppressor, suppresses growth and invasiveness of gastric cancer. Oncogene. 32:307–317. 2013. View Article : Google Scholar : PubMed/NCBI
9	Du W, Wang S, Zhou Q, et al: ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer. Oncogene. 32:3319–3328. 2013. View Article : Google Scholar : PubMed/NCBI
10	Yeung K, Seitz T, Li S, et al: Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature. 401:173–177. 1999. View Article : Google Scholar : PubMed/NCBI
11	Fu Z, Smith PC, Zhang L, et al: Effects of raf kinase inhibitor protein expression on suppression of prostate cancermetastasis. J Natl Cancer Inst. 95:878–889. 2003. View Article : Google Scholar : PubMed/NCBI
12	Al-Mulla F, Bitar MS, Thiery JP, et al: Clinical implications for loss or diminution of expression of Raf-1 kinase inhibitory protein and its phosphorylated form in ductal breast cancer. Am J Cancer Res. 3:446–464. 2013.PubMed/NCBI
13	Zebisch A, Wölfler A, Fried I, et al: Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia. Leukemia. 26:1842–1849. 2012. View Article : Google Scholar : PubMed/NCBI
14	Al-Mulla F, Hagan S, Behbehani AI, et al: Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. J Clin Oncol. 24:5672–5679. 2006. View Article : Google Scholar : PubMed/NCBI
15	Das SK, Bhutia SK, Sokhi UK, et al: Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma. Cancer Res. 72:6217–6226. 2012. View Article : Google Scholar : PubMed/NCBI
16	Zlobec I, Baker K, Minoo P, et al: Node-negative colorectal cancer at high risk of distant metastasis identified by combined analysis of lymph node status, vascular invasion, and Raf-1 kinase inhibitor protein expression. Clin Cancer Res. 14:143–148. 2008. View Article : Google Scholar
17	Beach S, Tang H, Park S, et al: Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene. 27:2243–2248. 2008. View Article : Google Scholar : PubMed/NCBI
18	Al-Mulla F, Bitar MS, Al-Maghrebi M, et al: Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Res. 71:1334–1343. 2011.PubMed/NCBI
19	Guo W, Dong Z, Guo Y, et al: Aberrant methylation and loss expression of RKIP is associated with tumor progression and poor prognosis in gastric cardia adenocarcinoma. Clin Exp Metastasis. 30:265–275. 2013. View Article : Google Scholar : PubMed/NCBI
20	Hamilton SR and Aaltonen LA: Pathology and genetics of tumours of the digestive system. World Health Organization Classification of Tumours. IARC Press; Lyon: 2000
21	Al-Mulla F, Hagan S, Al-Ali W, et al: Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instablility. J Clin Pathol. 61:524–529. 2008. View Article : Google Scholar : PubMed/NCBI
22	Chatterjee D, Sabo E, Tavares R and Resnick MB: Inverse association between Raf kinase inhibitory protein and signal transducers and activators of transcription 3 expression in gastric adenocarcinoma patients: implications for clinical outcome. Clin Cancer Res. 14:2994–3001. 2008. View Article : Google Scholar
23	Hsu YL, Chen CY, Lin IP, et al: 4-Shogaol, an active constituent of dietary ginger, inhibits metastasis of MDA-MB-231 human breast adenocarcinoma cells by decreasing the repression of NF-κB/Snail on RKIP. J Agric Food Chem. 60:852–861. 2012.PubMed/NCBI
24	Wu SC and Zhang Y: Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol. 11:607–620. 2010. View Article : Google Scholar : PubMed/NCBI
25	Guo W, Dong Z, Lin X, et al: Decreased expression and aberrant methylation of Raf kinase inhibitory protein gene in esophageal squamous cell carcinoma. Cancer Invest. 30:703–711. 2012. View Article : Google Scholar : PubMed/NCBI
26	Poma P, Labbozzetta M, Vivona N, et al: Analysis of possible mechanisms accounting for Raf-1 kinase inhibitor protein downregulation in hepatocellular carcinoma. OMICS. 16:579–588. 2012. View Article : Google Scholar : PubMed/NCBI
27	Martinho O, Gouveia A, Silva P, et al: Loss of RKIP expression is associated with poor survival in GISTs. Virchows Arch. 455:277–284. 2009. View Article : Google Scholar : PubMed/NCBI