Role of metadherin in estrogen-regulated gene expression.

Role of metadherin in estrogen-regulated gene expression.
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DOI:
10.3892/ijmm.2017.3020
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发表时间:
2017-08
影响因子:
5.4
通讯作者:
Meng X
Meng X
中科院分区:
医学3区
文献类型:
--
作者:
Li Y;Gonzalez Bosquet J;Yang S;Thiel KW;Zhang Y;Liu H;Leslie KK;Meng X

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雌激素信号的中断广泛地与乳腺癌、子宫内膜癌和卵巢癌的发生有关。作为一种多功能的肿瘤发生介质,基质粘附素/星形胶质细胞升高基因-1(AEG-1)的过度表达与多种肿瘤类型有关,已有报道在肿瘤的发生、增殖、侵袭、转移和化疗耐药中发挥作用。在分子水平上,mtdh与促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)以及葡萄球菌核酸酶和都铎结构域含有1(SNd1)。通过对雌激素受体(ER)阳性的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%的基因表达与MTDH相关。利用Affymetrix微阵列,我们研究了雌激素处理的双亲细胞和MTDH缺陷的子宫内膜癌细胞和乳腺癌细胞在基因表达上的差异。我们还通过免疫沉淀探索了MTDH和ER之间可能的相互作用,并发现在乳腺癌和子宫内膜癌细胞对雌激素的反应中,MTDH和ER都是相关的。相互免疫共沉淀分析表明,急性雌激素刺激促进了胞核内MTDH与ER的相互作用。这些数据,就我们所知,提供了第一个证据,表明mtdh和ERα在细胞核内与雌激素治疗相互作用,调节基因表达。
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.
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