Yang Qiwei, Mas Aymara, Diamond Michael P, Al-Hendy Ayman
Division of Translation Research, Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, GA, USA
Division of Translation Research, Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
Reprod Sci. 2016 Feb;23(2):163-75. doi: 10.1177/1933719115584449. Epub 2015 Apr 28.
Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and ten-eleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17β-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options.
子宫平滑肌瘤，也被称为子宫肌瘤，是最常见的盆腔肿瘤，在近70%的育龄妇女中都会出现，并且是全球范围内子宫切除术的主要指征。子宫平滑肌瘤的发生涉及激素、生长因子、干细胞、基因和表观遗传异常等复杂且异质性的因素组合。越来越多的证据强调表观遗传学在平滑肌瘤发病机制中的重要作用。全基因组甲基化分析表明，一部分雌激素受体（ER）反应基因表现出异常的高甲基化水平，这与它们的RNA表达呈负相关。与相邻正常组织相比，包括 Kruppel样因子11（KLF11）、肺癌和食管癌缺失基因1（DLEC1）、角蛋白19（KRT19）以及死亡相关蛋白激酶1（DAPK1）在内的一些肿瘤抑制基因在平滑肌瘤中也显示出更高的高甲基化水平。最近发现，关于十 - 十一易位蛋白1和十 - 十一易位蛋白3介导的平滑肌瘤中5 - 羟甲基胞嘧啶水平升高，活性DNA去甲基化起着重要作用。此外，据报道组蛋白脱乙酰酶和组蛋白甲基转移酶都参与了平滑肌瘤的生物学过程。在平滑肌瘤中已鉴定出许多失调的微小RNA，导致其靶标的表达发生改变。最近，在平滑肌瘤中已鉴定出具有肿瘤起始细胞特征的侧群（SP）细胞。当暴露于17β - 雌二醇和孕酮时，这些SP细胞在免疫缺陷小鼠中表现出致瘤能力，在体内产生肌瘤样组织。这些新发现可能会加深我们对表观遗传学在子宫平滑肌瘤发病机制中所起关键作用的理解，并为新的治疗选择指明方向。
