Ye Yan, Qian Xue Yi, Xiao Miao Miao, Shao Yu Ling, Guo Li Mei, Liao Dong Ping, Da Jie, Zhang Lin Jie, Xu Jiegou
Department of Immunology, Anhui Medical University, Hefei 230032, China.
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Int J Mol Sci. 2017 Jan 22;18(1):220. doi: 10.3390/ijms18010220.
Past studies have shown that the Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) is commonly downregulated in gastric cancer, which contributes to elevated activation of PI3K/Akt signaling, proliferation and tumorigenesis of gastric cancer cells. However, the mechanisms underlying the reduced expression of SHIP2 in gastric cancer remain unclear. While gene copy number variation analysis and exon sequencing indicated the absence of genomic alterations of , bisulfite genomic sequencing (BGS) showed promoter hypomethylation of in gastric cancer cells. Analysis of transcriptional activity of promoter revealed Specificity protein 1 (Sp1) was responsible for the regulation of SHIP2 expression in gastric cancer cells. Furthermore, Sp1 expression, but not Sp3, was frequently downregulated in gastric cancer compared with normal gastric mucosa, which was associated with a paralleled reduction in SHIP2 levels in gastric cancer. Moreover, overexpression of Sp1 inhibited cell proliferation, induced apoptosis, suppressed cell motility and invasion in gastric cancer cells in vitro, which was, at least in part, due to transcriptional activation of mediated by Sp1, thereby inactivating Akt. Collectively, these results indicate that decreased expression of transcription factor Sp1 contributes to suppression of SHIP2 in gastric cancer cells.
既往研究表明，含Src同源2结构域的肌醇5 -磷酸酶2（SHIP2）在胃癌中通常表达下调，这导致PI3K/Akt信号通路激活增强、胃癌细胞增殖及肿瘤发生。然而，SHIP2在胃癌中表达降低的潜在机制仍不清楚。虽然基因拷贝数变异分析和外显子测序表明不存在[具体基因]的基因组改变，但亚硫酸氢盐基因组测序（BGS）显示胃癌细胞中[具体基因]启动子低甲基化。对[具体基因]启动子转录活性的分析表明，特异性蛋白1（Sp1）负责调控胃癌细胞中SHIP2的表达。此外，与正常胃黏膜相比，Sp1而非Sp3的表达在胃癌中经常下调，这与胃癌中SHIP2水平的相应降低相关。而且，Sp1的过表达在体外抑制胃癌细胞增殖、诱导凋亡、抑制细胞迁移和侵袭，这至少部分是由于Sp1介导的[具体基因]转录激活，从而使Akt失活。总体而言，这些结果表明转录因子Sp1表达降低导致胃癌细胞中SHIP2受到抑制。
