Hong Ziqi, Mo Ting, Zhou Peiquan, Chen Jian, Li Xin
Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China.
Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China.
Front Endocrinol (Lausanne). 2025 Aug 25;16:1586191. doi: 10.3389/fendo.2025.1586191. eCollection 2025.
Endometrial cancer (EC) is one of the most common gynecological cancers in developed countries. Like EC, most female reproductive tract malignancies are thought to be hormonally driven, with estrogen signaling acting as an oncogenic signal. The actions of estrogen are mediated through the classical nuclear estrogen receptors α (ER-α) and β (ER-β) as well as transmembrane G protein-coupled estrogen receptors (GPR30 and GPER). Ligand-bound estrogen receptor (ER) and GPER trigger multiple downstream signaling pathways that regulate the cell cycle, differentiation, migration, and apoptosis in various tissues, including the endometrium. Additionally, growing evidence suggests that selective splicing events at the receptor result in multiple ERα proteins with different molecular weights and functional structural domains. Examples include ER-α66, ER-α46, and ER-α36. In addition, various post-translational modifications (PTMs) further affect ER-α cellular localization and ligand affinity, resulting in a change in the cellular function. These splice isoforms and PTMs are differentially expressed in a tissue-specific manner. They mediate some aspects of ER-α signaling and may even antagonize full-length ER-α. Therefore, both ER-α and its splice isoforms may play a role in the development of EC. In this review, we examine the influential roles of ER-α and ER-β, as well as the GPER estrogen signaling pathway, in EC. Our goal is to provide theoretical support for further research on the molecular mechanisms between ER and EC and to generate new ideas for the early diagnosis of EC and the development of new drugs.
子宫内膜癌（EC）是发达国家最常见的妇科癌症之一。与子宫内膜癌一样，大多数女性生殖道恶性肿瘤被认为是激素驱动的，雌激素信号传导充当致癌信号。雌激素的作用是通过经典的核雌激素受体α（ER-α）和β（ER-β）以及跨膜G蛋白偶联雌激素受体（GPR30和GPER）介导的。配体结合的雌激素受体（ER）和GPER触发多个下游信号通路，这些通路调节包括子宫内膜在内的各种组织中的细胞周期、分化、迁移和凋亡。此外，越来越多的证据表明，受体处的选择性剪接事件会产生多种具有不同分子量和功能结构域的ERα蛋白。例子包括ER-α66、ER-α46和ER-α36。此外，各种翻译后修饰（PTM）进一步影响ER-α的细胞定位和配体亲和力，导致细胞功能发生变化。这些剪接异构体和PTM以组织特异性方式差异表达。它们介导ER-α信号传导的某些方面，甚至可能拮抗全长ER-α。因此，ER-α及其剪接异构体都可能在子宫内膜癌的发生发展中起作用。在这篇综述中，我们研究了ER-α和ER-β以及GPER雌激素信号通路在子宫内膜癌中的影响作用。我们的目标是为进一步研究ER与子宫内膜癌之间的分子机制提供理论支持，并为子宫内膜癌的早期诊断和新药开发产生新的思路。
