C: Maspin genetically and functionally associates with gastric cancer by regulating cell cycle progression

Human SERPINB5, commonly known as maspin, has diverse functions as a tumor suppressor. In this study, we discovered that maspin has a novel role in cell cycle control, and common variants were discovered to be associated with gastric cancer. The geno-types of 836 unrelated Korean participants (including 430 with gastric cancer) were examined for 12 tag single-nucleotide poly-morphisms (SNPs) and imputed for 178 SNPs in the maspin gene. Susceptibility to diffuse-type gastric cancer was strongly and sig-nificantly associated with several SNPs including rs3744941 (C>T) in the promoter (TT versus CC+CT, odds ratio = 0.56 [0.37–0.83], P = 0.0038) and rs8089104 (C>T) in intron 1 (TT+CT versus CC, odds ratio = 1.7 [1.2–2.5], P = 0.0021). No SNPs were associated with susceptibility to intestinal-type gastric cancer. A haplotype of three highly correlated promoter SNPs associated with higher cancer risk showed 40 % of the activity of a non-risk-associated haplotype promoter in the diffuse-type gastric cancer cell line MKN45. Maspin downregulation achieved either by a short hair-pin RNA targeting maspin or overexpression of the E2F1-DP1 complex in MKN45 cells dramatically accelerated cell cycle pro-gression and caused an increase of active CDC25C levels and a decrease of inactive CDK1 levels. In contrast, maspin upregula-tion had the opposite effect, substantially retarding cell prolif-eration. Therefore, our results suggest that a maspin promoter haplotype that reduces maspin gene expression accelerates cell cycle progression and, consequently, is associated with increased susceptibility to diffuse-type gastric cancer. Furthermore, a novel maspin-related pathway is demonstrated to underlie gastric carcinogenesis