Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Int J Mol Med. 2017 Aug;40(2):303-310. doi: 10.3892/ijmm.2017.3020. Epub 2017 Jun 13.
The disruption of estrogen signaling is widely associated with the development of breast, endometrial and ovarian cancers. As a multifunctional mediator of carcinogenesis, metadherin (MTDH)/astrocyte elevated gene-1 (AEG-1) overexpression has been associated with numerous types of cancer, with reported roles in tumor initiation, proliferation, invasion, metastasis and chemoresistance. At the molecular level, MTDH has been shown to interact with proteins that drive tumorigenesis, including nuclear factor-κB (NF-κB), promyelocytic leukaemia zinc finger (PLZF), BRCA2- and CDKN1A (p21Cip1/Waf-1/mda-6)-interacting protein α (BCCIPα) and staphylococcal nuclease and tudor domain containing 1 (SND1). Through the analysis of the Cancer Genome Atlas (TCGA) datasets for estrogen receptor (ER)-positive endometrial and breast cancers, we found that over 25% of all gene expression correlated with MTDH. Using Affymetrix microarrays, we characterized the differences in gene expression between estrogen-treated parental and MTDH-deficient endometrial and breast cancer cells. We also explored a possible interaction between MTDH and ER by immunoprecipitation, and found that MTDH and ER associated in both breast and endometrial cancer cells in response to estrogen. Reciprocal co-immunoprecipitation analysis demonstrated that acute estrogen stimulation promoted the interaction of MTDH with ER in the nucleus. These data, to the best of our knowledge, provide the first evidence that MTDH and ERα interact in the nucleus with estrogen treatment to regulate gene expression.
雌激素信号的中断与乳腺癌、子宫内膜癌和卵巢癌的发展广泛相关。作为致癌作用的多功能介质，间变性淋巴瘤激酶（MTDH）/星形细胞瘤上调基因-1（AEG-1）过表达与多种类型的癌症相关，其作用包括肿瘤起始、增殖、侵袭、转移和化疗耐药。在分子水平上，已经表明 MTDH 与驱动肿瘤发生的蛋白质相互作用，包括核因子-κB（NF-κB）、早幼粒细胞白血病锌指（PLZF）、BRCA2 和 CDKN1A（p21Cip1/Waf-1/mda-6）相互作用蛋白α（BCCIPα）和葡萄球菌核酸酶和 tudor 结构域包含 1（SND1）。通过对雌激素受体（ER）阳性子宫内膜癌和乳腺癌的癌症基因组图谱（TCGA）数据集的分析，我们发现超过 25%的所有基因表达与 MTDH 相关。使用 Affymetrix 微阵列，我们对雌激素处理的亲本和 MTDH 缺陷子宫内膜癌和乳腺癌细胞之间的基因表达差异进行了特征描述。我们还通过免疫沉淀探索了 MTDH 和 ER 之间可能的相互作用，发现 MTDH 和 ER 在雌激素作用下与乳腺癌和子宫内膜癌细胞相关。相互共免疫沉淀分析表明，急性雌激素刺激促进了 MTDH 与 ER 在核内的相互作用。据我们所知，这些数据首次提供了证据，表明 MTDH 和 ERα 在细胞核内与雌激素一起相互作用以调节基因表达。
