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Objective.Urokinase (uPA) is expressed in a number of highly invasive malignancies including gastric cancer. Production of uPA is associated with tumor progression and therefore it can serve as a useful prognostic marker for invasive cancers. The objective of this study was to examine the role of uPA promoter methylation as an indicator of uPA production in gastric cancer patients and cell-lines

Design and Methods. Methylation status of the uPA promoter in human gastric cancer cells with various invasiveness and in surgical biopsy samples of gastric adenocarcinoma and surrounding tissues from gastric cancer patients was examined by methylation specific PCR and bisulfite sequencing analysis. uPA mRNA was measured by real-time quantitative PCR. Associations between the methylation status, expression of uPA and clinical-pathological outcomes in patients were also examined.

Results. Analysis of biopsy samples showed that elevated expression of uPA was detected in 42 out of 48 gastric tumor compared to their surrounding tissues. Hypomethylation of the uPA promoter is directly associated with elevated uPA expression that was associated with advanced tumor stage, depth of invasion, occurrence of serosa invasion and lymphnode metastasis. Hypomethylation of the uPA promoter is also found related to elevated uPA expression and increased invasiveness in human gastric cancer cell-lines; and demethylation of the uPA promoter could induce uPA expression and enzyme activity in gastric cancer cells.

Conclusions. This study indicated that uPA expression in gastric tumor is under epigenetic control via methylation of its promoter. Determination of uPA promoter methylation could therefore serve as an early prognostic indicator of uPA production and cancer progression in patients with gastric adenocarcinoma (Support by TCVGH-NCHU 947607 and NSC95-2320-B-005-008-MY3).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA