Abnormal reduction of the level of RKIP expression was frequently detected in the cancercell lines and primary tumortissues, at both the transcript and protein levels. Moreover, the expression level of RKIP in the tumorcells 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 cancercell 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 humangastric 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.