Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Evolution and Reproductive Medicine, Medical Mycology Research Center, Chiba University, Chiba, Japan.
J Mol Endocrinol. 2023 Sep 29;71(4). doi: 10.1530/JME-23-0039. Print 2023 Nov 1.
Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. Women with symptomatic UFs have reduced quality of life and decreased labor productivity. Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs. MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/β-catenin signaling are identified in MED12-UFs. Clinically, the UF shrinking effect of gonadotropin-releasing hormone agonists and ulipristal acetate is dependent on the MED12 mutation status. Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.
子宫肌瘤（UFs）是源自子宫的良性肿瘤，其特征是大量细胞外基质（ECM）的积累和性激素依赖性生长。有症状的 UFs 妇女生活质量降低，劳动力生产率下降。在 UFs 中鉴定出的驱动基因突变中，MED12 突变是最常见的，也是 cyclin-dependent kinase (CDK) Mediator 模块的一个组成部分，在 50-80%的 UFs 中观察到。它们是功能获得性突变，在黑人妇女中更为常见，甚至在小的 UFs 中也很常见。MED12 突变阳性的 UFs（MED12-UFs）通常是多发性的，而不是单发的，并且具有独特的基因表达谱、DNA 甲基化组、转录组和蛋白质组。与 ECM 组织和富含胶原蛋白的 ECM 成分相关的基因表达上调，并且在 MED12-UFs 中鉴定到 Mediator 激酶活性受损和 Wnt/β-catenin 信号通路失调。临床上，促性腺激素释放激素激动剂和 ulipristal 乙酸对 UF 的缩小作用取决于 MED12 突变状态。对 MED12-UFs 的特征和 MED12 突变对 UF 肿瘤发生的功能的理解可能阐明 UFs 的病理生理学，为有症状的 UFs 妇女开发新的治疗选择。
