Research Laboratory in Biomarkers in Reproduction, Obstetrics and Gynecology, Research Foundation of the General University Hospital of Valencia, 46014 Valencia, Spain.
Bioinformatics and Genomics Department, Saphetor SA, 1015 Lausanne, Switzerland.
Cells. 2024 Nov 18;13(22):1904. doi: 10.3390/cells13221904.
High-grade serous ovarian cancer (HGSOC) is the most lethal form of gynecologic cancer, with limited treatment options and a poor prognosis. Epigenetic factors, such as microRNAs (miRNAs) and DNA methylation, play pivotal roles in cancer progression, yet their specific contributions to HGSOC remain insufficiently understood. In this study, we performed comprehensive high-throughput analyses to identify dysregulated miRNAs in HGSOC and investigate their epigenetic regulation. Analysis of tissue samples from advanced-stage HGSOC patients revealed 20 differentially expressed miRNAs, 11 of which were corroborated via RT-qPCR in patient samples and cancer cell lines. Among these, miR-145-3p was consistently downregulated post-neoadjuvant therapy and was able to distinguish tumoural from control tissues. Further investigation confirmed that DNA methylation controls expression. Functional assays showed that overexpression of miR-145-3p significantly reduced cell migration and induced G0/G1 cell cycle arrest by modulating the cyclin D1-CDK4/6 pathway. These findings suggest that miR-145-3p downregulation enhances cell proliferation and motility in HGSOC, implicating its restoration as a potential therapeutic target focused on G1/S phase regulation in the treatment of HGSOC.
高级别浆液性卵巢癌（HGSOC）是最致命的妇科癌症形式，治疗选择有限，预后不良。表观遗传因素，如 microRNAs（miRNAs）和 DNA 甲基化，在癌症进展中起着关键作用，但它们对 HGSOC 的具体贡献仍了解不足。在这项研究中，我们进行了全面的高通量分析，以鉴定 HGSOC 中失调的 miRNAs，并研究其表观遗传调控。对晚期 HGSOC 患者组织样本的分析显示了 20 个差异表达的 miRNAs，其中 11 个通过 RT-qPCR 在患者样本和癌细胞系中得到了证实。其中，miR-145-3p 在新辅助治疗后一直下调，并且能够区分肿瘤组织和对照组织。进一步的研究证实，DNA 甲基化控制其表达。功能测定表明，miR-145-3p 的过表达通过调节细胞周期蛋白 D1-CDK4/6 途径显著降低细胞迁移并诱导 G0/G1 细胞周期停滞。这些发现表明，miR-145-3p 的下调增强了 HGSOC 中的细胞增殖和迁移，暗示其恢复可能是针对 HGSOC 中 G1/S 期调控的潜在治疗靶点。
