Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, Arkansas 72202, USA.
J Endocrinol. 2010 May;205(2):147-57. doi: 10.1677/JOE-09-0474. Epub 2010 Feb 17.
Inappropriate early exposure of the hormone-responsive uterus to estrogenic compounds is associated with increased risk for adult reproductive diseases including endometrial cancers. While the dysregulation of estrogen receptor-alpha (ESR1) signaling is well acknowledged to mediate early events in tumor initiation, mechanisms contributing to sustained ESR1 activity later in life and leading to induction of oncogenic pathways remain poorly understood. We had shown previously that the transcription factor Krüppel-like factor 9 (KLF9) represses ESR1 expression and activity in Ishikawa endometrial glandular epithelial cells. We hypothesized that KLF9 functions as a tumor suppressor, and that loss of its expression enhances ESR1 signaling. Here, we evaluated the contribution of KLF9 to early perturbations in uterine ESR1 signaling pathways elicited by the administration of synthetic estrogen diethylstilbestrol (DES) to wild-type (WT) and Klf9 null (KO) mice on postnatal days (PNDs) 1-5. Uterine tissues collected at PND84 were subjected to histological, immunological, and molecular analyses. Compared with WT mice, KO mice demonstrated larger endometrial glands and lower endometrial gland numbers; DES exposure exacerbated these differences. Loss of KLF9 expression resulted in increased glandular ESR1 immunoreactivity with DES, without effects on serum estradiol levels. Quantitative RT-PCR analyses indicated altered expression of uterine genes commonly dysregulated in endometrial cancers (Akt1, Mmp9, Slpi, and Tgfbeta1) and of those involved in growth regulation (Fos, Myc, Tert, and Syk), with loss of Klf9, alone or in concert with DES. Our data support a molecular network between KLF9 and ESR1 in the uterus, and suggest that silencing of KLF9 may contribute to endometrial dysfunctions initiated by aberrant estrogen action.
不适当的早期暴露于雌激素化合物的激素反应性子宫与成年生殖系统疾病的风险增加有关，包括子宫内膜癌。虽然雌激素受体-α（ESR1）信号的失调被认为很好地介导了肿瘤起始的早期事件，但导致 ESR1 活性持续存在并导致致癌途径诱导的机制仍知之甚少。我们之前已经表明，转录因子 Krüppel 样因子 9（KLF9）在 Ishikawa 子宫内膜腺上皮细胞中抑制 ESR1 的表达和活性。我们假设 KLF9 作为肿瘤抑制因子发挥作用，并且其表达的丧失增强了 ESR1 信号。在这里，我们评估了 KLF9 对新生后第 1-5 天给予合成雌激素己烯雌酚（DES）后子宫 ESR1 信号通路早期扰动的贡献，在野生型（WT）和 Klf9 缺失（KO）小鼠上。在 PND84 收集的子宫组织进行组织学、免疫学和分子分析。与 WT 小鼠相比，KO 小鼠表现出更大的子宫内膜腺和更低的子宫内膜腺数量；DES 暴露加剧了这些差异。KLF9 表达的丧失导致 DES 诱导的子宫内膜腺中 ESR1 免疫反应性增加，而对血清雌二醇水平没有影响。定量 RT-PCR 分析表明，子宫基因的表达发生改变，这些基因通常在子宫内膜癌中失调（Akt1、Mmp9、Slpi 和 Tgfbeta1），以及那些参与生长调节的基因（Fos、Myc、Tert 和 Syk），而 Klf9 的缺失，无论是单独缺失还是与 DES 协同缺失。我们的数据支持子宫中 KLF9 和 ESR1 之间的分子网络，并表明 KLF9 的沉默可能导致由异常雌激素作用引发的子宫内膜功能障碍。
