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Clinical Significance of CD99 Down-Regulation in Gastric Adenocarcinoma

Authors' Affiliations: ¹ Department of Pharmacy, Research Institute of Pharmaceutical Science, Seoul National University College of Pharmacy; ² Department of Statistics, College of Nature Science, Seoul National University; ³ Department of Preventive Medicine, Seoul National University College of Medicine; ⁴ Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; ⁵ Department of Pathology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and ⁶ Department of Pharmacology, Shenyang Pharmaceutical University College of Pharmacy, Shenyang, China

Requests for reprints: Young Kee Shin, Molecular Pathology Laboratory, Department of Pharmacy, Seoul National University College of Pharmacy, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, Korea. Phone: 82-2-880-9126; Fax: 82-2-872-1795; E-mail: ykeeshin{at}snu.ac.kr.

Purpose: CD99 is a cell adhesion molecule associated with human tumors. The aim of the present study was to characterize its role in the development and progression of human gastric adenocarcinoma.

Experimental Design: The expression of CD99 was investigated in 283 gastric adenocarcinomas and related lesions and 9 gastric carcinoma cell lines. We also analyzed the methylation status of CD99 gene by using methylation-specific PCR and examined loss of heterozygosity (LOH) of this gene locus by using an intragenic marker. Moreover, we assessed whether SP1, a positive transcription factor for CD99, is expressed in these samples.

Results: We found that the decreased expression of CD99 was strongly associated with poor survival and unfavorable clinicopathologic variables. Promoter region methylation (15 of 89, 16.9%) and LOH (21 of 74, 28.4%) were observed and significantly associated with CD99 down-regulation (P < 0.05). In addition, most of the gastric adenocarcinoma cases with CD99 down-regulation had reduced expression of SP1 (47 of 103, 45.6%; P < 0.01). This relationship between CD99 and SP1 was consolidated by using SP1 small interfering RNA transfection experiment and CD99 promoter luciferase assay. Furthermore, we showed that CD99 down-regulation was associated with proliferation and migration in gastric carcinoma cell line.

Conclusion: These observations suggest that CD99 down-regulation is a critical event in the progression of gastric adenocarcinoma, and CD99 promoter methylation, CD99 LOH, and SP1 down-regulation were responsible for the down-regulation of CD99.