Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Cancer. 2011 Nov 15;117(22):5161-71. doi: 10.1002/cncr.26161. Epub 2011 Apr 26.
The runt-related transcription factor RUNX3 plays essential roles in various types of tumors, including gastric cancer. Epigenetic changes in the methylation of the RUNX3 proximal promoter, but not common genetic changes in RUNX3, have been associated with both changes in the gene expression and development of the cancer.
A case-control association study was conducted by genotyping 865 unrelated Korean subjects. Subsequent functional studies were performed to reveal functional implication of genetic association.
Several single-nucleotide polymorphisms (SNPs) in RUNX3 were significantly associated with susceptibility to intestinal-type gastric cancer (.0028 ≤ P ≤ .022) but not diffuse-type gastric cancer (.70 ≤ P ≤ .96). The risk-associated, minor variant of an intestinal-type gastric cancer-associated SNP in the RUNX3 distal promoter (rs7528484) significantly increased promoter activity in a CREB1-dependent manner. The distal promoter-derived, 33 kDa isoform of RUNX3 increased the activity of transcription factor nuclear factor kappa B (NF-κB), which had been activated by Helicobacter pylori infection, a risk factor for intestinal-type gastric cancer, and the expression of the interleukin-1β gene (IL1B), an NF-κB target genetically and functionally associated with gastric cancer. In contrast, the proximal promoter-derived, 44 kDa isoform of RUNX3 decreased both NF-κB activity and IL1B expression.
In addition to epigenetic changes in the RUNX3 proximal promoter, genetic changes in the distal promoter may be associated with susceptibility to intestinal-type gastric cancer by increasing promoter activity. Functionally, 2 RUNX3 isoforms may contribute differentially to intestinal-type gastric cancer susceptibility, at least in part through regulating NF-κB activity and IL1B expression.
runt 相关转录因子 RUNX3 在包括胃癌在内的多种类型的肿瘤中发挥着重要作用。RUNX3 近端启动子的甲基化等表观遗传变化，而不是 RUNX3 的常见遗传变化，与基因表达的变化和癌症的发展有关。
通过对 865 名无关韩国个体进行基因分型，进行病例对照关联研究。随后进行了功能研究，以揭示遗传关联的功能意义。
RUNX3 中的几个单核苷酸多态性（SNP）与肠型胃癌的易感性显著相关（.0028 ≤ P ≤.022），但与弥漫型胃癌无关（.70 ≤ P ≤.96）。RUNX3 远端启动子中与肠型胃癌相关的 SNP 的风险相关的、次要的变体（rs7528484）以 CREB1 依赖性方式显著增加启动子活性。RUNX3 远端启动子衍生的 33 kDa 同工型增加了转录因子核因子 kappa B（NF-κB）的活性，NF-κB 已被幽门螺杆菌感染激活，这是肠型胃癌的一个危险因素，并且白细胞介素-1β基因（IL1B）的表达，IL1B 是一个在遗传和功能上与胃癌相关的 NF-κB 靶基因。相比之下，近端启动子衍生的 44 kDa 同工型降低了 NF-κB 活性和 IL1B 表达。
除了 RUNX3 近端启动子的表观遗传变化外，远端启动子的遗传变化也可能通过增加启动子活性与肠型胃癌的易感性相关。在功能上，2 种 RUNX3 同工型可能通过调节 NF-κB 活性和 IL1B 表达，不同程度地促进肠型胃癌的易感性。
