Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Carcinogenesis. 2012 Dec;33(12):2344-50. doi: 10.1093/carcin/bgs280. Epub 2012 Sep 7.
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 genotypes of 836 unrelated Korean participants (including 430 with gastric cancer) were examined for 12 tag single-nucleotide polymorphisms (SNPs) and imputed for 178 SNPs in the maspin gene. Susceptibility to diffuse-type gastric cancer was strongly and significantly 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 hairpin RNA targeting maspin or overexpression of the E2F1-DP1 complex in MKN45 cells dramatically accelerated cell cycle progression and caused an increase of active CDC25C levels and a decrease of inactive CDK1 levels. In contrast, maspin upregulation had the opposite effect, substantially retarding cell proliferation. 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.
人源丝氨酸蛋白酶抑制剂 B5（SERPINB5），通常被称为 maspin，作为一种肿瘤抑制因子具有多种功能。在这项研究中，我们发现 maspin 在细胞周期调控中具有新的作用，并且常见的变体与胃癌相关。对 836 名无亲缘关系的韩国参与者（包括 430 名胃癌患者）的 12 个标签单核苷酸多态性（SNP）进行了基因型检测，并对 maspin 基因中的 178 个 SNP 进行了推断。弥漫型胃癌的易感性与包括启动子 rs3744941（C>T）（TT 与 CC+CT 相比，比值比=0.56[0.37-0.83]，P=0.0038）和内含子 1 rs8089104（C>T）（TT+CT 与 CC 相比，比值比=1.7[1.2-2.5]，P=0.0021）在内的几个 SNP 显著相关。没有 SNP 与肠型胃癌的易感性相关。与较高癌症风险相关的三个高度相关启动子 SNP 的单倍型显示，弥漫型胃癌细胞系 MKN45 中，非风险相关单倍型启动子的活性降低了 40%。通过靶向 maspin 的短发夹 RNA 下调 maspin 表达或在 MKN45 细胞中过表达 E2F1-DP1 复合物，均可显著加速细胞周期进程，并导致活性 CDC25C 水平升高和非活性 CDK1 水平降低。相反，上调 maspin 则产生相反的效果，显著减缓细胞增殖。因此，我们的结果表明，降低 maspin 基因表达的 maspin 启动子单倍型可加速细胞周期进程，从而与弥漫型胃癌的易感性增加相关。此外，还证明了一种新的与 maspin 相关的途径是胃癌发生的基础。
