Jia Zanhui, Gao Shuping, M'Rabet Nadira, De Geyter Christian, Zhang Hong
Clinic of Gynecological Endocrinology and Reproductive Medicine, University of Basel, Spitalstrasse 21, CH-4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland; Department of Gynecology and Obstetrics, Second Hospital of Jilin University, Changchun City, Jilin Province, P.R. China.
J Cell Biochem. 2014 Oct;115(10):1829-39. doi: 10.1002/jcb.24855.
Adamts17 is a member of a family of secreted metalloproteinases. In this report, we show that knockdown of Adamts17 expression induces apoptosis and inhibits breast cancer cell growth. Adamts17 expression can rapidly be induced by estrogens. siRNA knockdown of Sp1 or Myc demonstrated that Sp1 is required to induce Adamts17 gene expression in response to estrogen. Moreover, reporter assays showed that the proximal promoter and the upstream sequences were not capable of conferring estrogen responsiveness, suggesting that Sp1 elements may be located in the downstream intronic region. We further demonstrated that Sp1 and Myc binding in the proximal promoter region contributed to the Adamts17 basal expression. Furthermore, histone deacetylase (HDAC) and methylase inhibitors also induced Adamts17 expression, indicating that epigenetic alterations, such as aberrant HDAC and/or methylation are associated with dysregulated Adamts17 expression. By meta-analysis using Oncomine microarray data, we found that higher Adamts17 expression is found in several human cancer cell subtypes, especially in breast ductal carcinoma. Moreover, we found that there is an inverse correlation between higher Adamts17 expression and patients' survival. Our study suggests that Adamts17 may support breast cancer cell growth and survival.
Adamts17是分泌型金属蛋白酶家族的一员。在本报告中，我们表明敲低Adamts17表达可诱导细胞凋亡并抑制乳腺癌细胞生长。Adamts17表达可被雌激素迅速诱导。对Sp1或Myc进行小干扰RNA敲低表明，Sp1是雌激素诱导Adamts17基因表达所必需的。此外，报告基因检测显示近端启动子和上游序列不具备赋予雌激素反应性的能力，这表明Sp1元件可能位于下游内含子区域。我们进一步证明，近端启动子区域中Sp1和Myc的结合有助于Adamts17的基础表达。此外，组蛋白脱乙酰酶（HDAC）和甲基化酶抑制剂也可诱导Adamts17表达，这表明表观遗传改变，如异常的HDAC和/或甲基化与Adamts17表达失调有关。通过使用Oncomine微阵列数据进行荟萃分析，我们发现在几种人类癌细胞亚型中，尤其是在乳腺导管癌中，Adamts17表达较高。此外，我们发现Adamts17高表达与患者生存率呈负相关。我们的研究表明，Adamts17可能支持乳腺癌细胞的生长和存活。
