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KMID : 0371320070730020121
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Journal of the Korean Surgical Society
2007 Volume.73 No. 2 p.121 ~ p.129
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Expression and Mutation Analysis of RKIP (Raf-1 Kinase Inhibitor Protein) in Human Gastric Cancer
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Chang Yeon-Soo
Lee Kil-Yeon
Lee Seok-Hwan
Koh Suck-Hwan
Hong Sung-Wha
Chi Sung-Gil
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Abstract
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Purpose: RKIP (Raf kinase inhibitor protein) is a novel candidate tumor suppressor, known to inhibit the MAPK signaling by interfering with the MEK phosphorylation by Raf-1. The aim of this study was to investigate the expression of RKIP and analyze the pattern of inactivation and mutation of the RKIP gene in human gastric cancer.
Methods: To explore if RKIP inactivation is implicated in gastric tumorigenesis, an expression analysis on the transcription and protein expression levels and a mutational analysis of RKIP were performed in 15 human gastric cancer cell lines and 92 primary carcinoma tissues.
Results: Abnormal reduction of the level of RKIP expression was frequently detected in the cancer cell lines and primary tumor tissues, at both the transcript and protein levels. Moreover, the expression level of RKIP in the tumor cells was inversely correlated with the level of Erk phosphorylation, indicating that RKIP plays a key role in the regulation of the Raf-MEK-Erk signaling pathway in human gastric cells. While the expression of the RKIP transcript was not re-activated in low expressor cells by treatment with the demethylating agent 5’Aza-dC, the genomic RKIP was detected at low levels in many cancer cell lines, suggesting that an abnormal reduction of level of RKIP expression in tumors might be caused by allelic deletion of the gene rather than transcriptional silencing due to aberrant DNA hypermethylation. A loss of heterozygosity study, using an intragenic polymorphic marker, revealed that approximately 21% of the gastric cancers harbored allelic loss of the RKIP gene.
Conclusion: Collectively, this study has demonstrated that RKIP is a tumor suppressor, whose expression is frequently downregulated by allelic deletion in human gastric cancers. This study also suggests that an altered expression of RKIP might contribute to the development of gastric cancer via abnormal elevation of the Raf-Erk signaling pathway. (J Korean Surg Soc 2007;73:121-129)
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KEYWORD
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Gastric cancer, Raf-1 kinase inhibitor protein, LOH
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