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Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

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

Requests for reprints: Young Kee Shin, Molecular Pathology Laboratory, College of Pharmacy, Department of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, Korea. Phone: 82-2880-9126; Fax: 82-2872-1795; E-mail: ykeeshin{at}snu.ac.kr.

Purpose: Mothers against decapentaplegic homologue 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis. The aim of the present study is to more precisely characterize its role in the development and progression of human gastric carcinoma.

Experimental Design: The expression of SMAD4 was investigated in 283 gastric adenocarcinomas and related lesions, as well as in 9 gastric carcinoma cell lines. We also analyzed the methylation status of SMAD4 gene by using methylation-specific PCR, examined loss of heterozygosity (LOH) of this gene locus by using a vicinal marker, and detected exon mutation of SMAD4 through exon-by-exon amplification. Moreover, we assessed whether MG132, a proteasome inhibitor, affected the SMAD4 protein level.

Results: We found loss of SMAD4 protein expression in the cytoplasm (36 of 114, 32%) and in the nucleus (46 of 114, 40%) of gastric cancer cells. The loss of nuclear SMAD4 expression in primary tumors correlated significantly with poor survival, and was an independent prognostic marker in multivariate analysis. We also found a substantial decrease in SMAD4 expression at both the RNA and protein level in several human gastric carcinoma cell lines. In addition, we found that LOH (20 of 70, 29%) and promoter hypermethylation (4 of 73, 5%) were associated with the loss of SMAD4 expression. SMAD4 protein levels were also affected in certain gastric carcinoma cell lines following incubation with MG132.

Conclusion: Taken together, our results indicate that the loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. The loss of SMAD4 in gastric carcinomas was due to several mechanisms, including LOH, hypermethylation, and proteasome degradation.

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