Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain.
J Pathol. 2022 Aug;257(5):663-673. doi: 10.1002/path.5920. Epub 2022 Jun 13.
Uterine leiomyomas (ULs) are the most common benign tumors in women of reproductive age. Despite the high prevalence, tumor pathology remains unclear, which hampers the development of safe and effective treatments. Epigenetic mechanisms appear to be involved in UL development, particularly via DNA methylation that regulates gene expression. We aimed to determine the relationship between DNA methylation and gene expression in UL compared with adjacent myometrium (MM) to identify molecular mechanisms involved in UL formation that are under epigenetic control. Our results showed a different DNA methylation profile between UL and MM, leading to hypermethylation of UL, and a different global transcriptome profile. Integration of DNA methylation and whole-transcriptome RNA-sequencing data identified 93 genes regulated by methylation, with 22 hypomethylated/upregulated and 71 hypermethylated/downregulated. Functional enrichment analysis showed dysregulated biological processes and molecular functions involved in metabolism and cell physiology, response to extracellular signals, invasion, and proliferation, as well as pathways related to uterine biology and cancer. Cellular components such as cell membranes, vesicles, extracellular matrix, and cell junctions were dysregulated in UL. In addition, we found hypomethylation/upregulation of oncogenes (PRL, ATP8B4, CEMIP, ZPMS2-AS1, RIMS2, TFAP2C) and hypermethylation/downregulation of tumor suppressor genes (EFEMP1, FBLN2, ARHGAP10, HTATIP2), which are related to proliferation, invasion, altered metabolism, deposition of extracellular matrix, and Wnt/β-catenin pathway dysregulation. This confirms that key processes of UL development are under DNA methylation control. Finally, inhibition of DNA methyltransferases by 5-aza-2'-deoxycitidine increased the expression of hypermethylated/downregulated genes in UL cells in vitro. In conclusion, gene regulation by DNA methylation is implicated in UL pathogenesis, and reversion of this methylation could offer a therapeutic option for UL. © 2022 The Pathological Society of Great Britain and Ireland.
子宫平滑肌瘤（UL）是育龄妇女中最常见的良性肿瘤。尽管患病率很高，但肿瘤病理学仍不清楚，这阻碍了安全有效的治疗方法的发展。表观遗传机制似乎参与了 UL 的发展，特别是通过调节基因表达的 DNA 甲基化。我们旨在确定 UL 与相邻子宫肌层（MM）相比，DNA 甲基化与基因表达之间的关系，以鉴定受表观遗传控制的 UL 形成中涉及的分子机制。我们的研究结果显示 UL 和 MM 之间存在不同的 DNA 甲基化谱，导致 UL 过度甲基化，以及不同的全转录组谱。DNA 甲基化和全转录组 RNA-seq 数据的整合确定了 93 个受甲基化调控的基因，其中 22 个低甲基化/上调和 71 个高甲基化/下调。功能富集分析显示，代谢和细胞生理学、细胞对外界信号的反应、侵袭和增殖以及与子宫生物学和癌症相关的途径中的生物学过程和分子功能失调。UL 中细胞的细胞膜、囊泡、细胞外基质和细胞连接等细胞成分失调。此外，我们发现致癌基因（PRL、ATP8B4、CEMIP、ZPMS2-AS1、RIMS2、TFAP2C）的低甲基化/上调和抑癌基因（EFEMP1、FBLN2、ARHGAP10、HTATIP2）的高甲基化/下调，这些基因与增殖、侵袭、代谢改变、细胞外基质沉积以及 Wnt/β-catenin 途径失调有关。这证实了 UL 发育的关键过程受到 DNA 甲基化的控制。最后，5-氮杂-2'-脱氧胞苷抑制 DNA 甲基转移酶可增加体外 UL 细胞中高甲基化/下调基因的表达。总之，DNA 甲基化对基因的调控参与了 UL 的发病机制，这种甲基化的逆转可能为 UL 提供一种治疗选择。
