Mahajan Vishakha, Gujral Palak, Jain Lekha, Ponnampalam Anna P
The Liggins Institute, University of Auckland, Auckland, New Zealand.
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Front Oncol. 2022 Mar 11;12:763464. doi: 10.3389/fonc.2022.763464. eCollection 2022.
Steroid hormones govern the complex, cyclic changes of the endometrium, predominantly through their receptors. An interplay between steroid hormones and epigenetic mechanisms controls the dynamic endometrial gene regulation. Abnormalities in expression of genes and enzymes associated with steroid hormone signaling, contribute to a disturbed hormonal equilibrium. Limited evidence suggests the involvement of TET (Ten Eleven Translocation)-mediated DNA hydroxymethylation in endometrial cancer, with some data on the use of TET1 as a potential prognostic and diagnostic biomarker, however the mechanisms guiding it and its regulation remains unexplored. This study aims to explore the changes in the expressions of TETs and steroid hormone receptors in response to estrogen and progesterone in endometrial cancer cells. Gene expression was examined using real-time PCR and protein expression was quantified using fluorescent western blotting in endometrial cancer cell lines (AN3 and RL95-2). Results indicate that TET1 and TET3 gene and protein expression was cell-specific in cancer cell-lines. Protein expression of TET1 was downregulated in AN3 cells, while TET1 and TET3 expressions were both upregulated in RL95-2 cells in response to estrogen-progesterone. Further, a decreased AR expression in AN3 cells and an increased ERα and ERβ protein expressions in RL95-2 cells was seen in response to estrogen-progesterone. PR gene and protein expression was absent from both cancer cell-lines. Overall, results imply that expressions of steroid hormones, steroid-hormone receptors and TETs are co-regulated in endometrial cancer-cells. Further studies are needed to interpret how these mechanisms fit in with DNMTs and DNA methylation in regulating endometrial biology. Understanding the role of TETs and hydroxymethylation in steroid hormone receptor regulation is crucial to comprehend how these mechanisms work together in a broader context of epigenetics in the endometrium and its pathologies.
类固醇激素主要通过其受体调控子宫内膜复杂的周期性变化。类固醇激素与表观遗传机制之间的相互作用控制着子宫内膜基因的动态调控。与类固醇激素信号传导相关的基因和酶表达异常会导致激素平衡紊乱。有限的证据表明，TET（十一-易位）介导的DNA羟甲基化与子宫内膜癌有关，有一些关于使用TET1作为潜在预后和诊断生物标志物的数据，然而，其指导机制及其调控仍未得到探索。本研究旨在探讨子宫内膜癌细胞中TETs和类固醇激素受体表达对雌激素和孕激素的反应变化。在子宫内膜癌细胞系（AN3和RL95-2）中，使用实时PCR检测基因表达，使用荧光western印迹法定量蛋白质表达。结果表明，TET1和TET3基因及蛋白质表达在癌细胞系中具有细胞特异性。在AN3细胞中，TET1的蛋白质表达下调，而在RL95-2细胞中，TET1和TET3的表达在雌激素-孕激素作用下均上调。此外，在雌激素-孕激素作用下，AN3细胞中的AR表达降低，而RL95-2细胞中的ERα和ERβ蛋白质表达增加。两种癌细胞系中均未检测到PR基因和蛋白质表达。总体而言，结果表明类固醇激素、类固醇激素受体和TETs的表达在子宫内膜癌细胞中共同调控。需要进一步研究来解释这些机制如何与DNA甲基转移酶和DNA甲基化协同作用以调节子宫内膜生物学。了解TETs和羟甲基化在类固醇激素受体调控中的作用对于理解这些机制如何在子宫内膜及其病理的表观遗传学更广泛背景下共同发挥作用至关重要。
