Departments of Pathology and Bio-Bank, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
Institute of Embryo-Fetal Original Adult Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
Cell Death Dis. 2018 Jan 24;9(2):94. doi: 10.1038/s41419-017-0108-2.
Gestational trophoblastic disease (GTD) encompasses a range of trophoblast-derived disorders. The most common type of GTD is hydatidiform mole (HM). Some of HMs can further develop into malignant gestational trophoblastic neoplasia (GTN). Aberrant expression of microRNA (miRNA) is widely reported to be involved in the initiation and progression of cancers. MiRNA expression profile also has been proved to be the useful signature for diagnosis, staging, prognosis, and response to chemotherapy. Till now, the profile of miRNA in the progression of GTD has not been determined. In this study, a total of 34 GTN and 60 complete HMs (CHM) trophoblastic tissues were collected. By miRNA array screening and qRT-PCR validating, six miRNAs, including miR-370-3p, -371a-5p, -518a-3p, -519d-3p, -520a-3p, and -934, were identified to be differentially expressed in GTN vs. CHM. Functional analyses further proved that miR-371a-5p and miR-518a-3p promoted proliferation, migration, and invasion of choriocarcinoma cells. Moreover, we demonstrated that miR-371a-5p was negatively related to protein levels of its predictive target genes BCCIP, SOX2, and BNIP3L, while miR-518a-3p was negatively related to MST1 and EFNA4. For the first time, we proved that miR-371a-5p and miR-518a-3p directly targeted to 3'-UTR regions of BCCIP and MST1, respectively. Additionally, we found that miR-371a-5p and miR-518a-3p regulated diverse pathways related to tumorigenesis and metastasis in choriocarcinoma cells. The results presented here may offer new clues to the progression of GTD and may provide diagnostic biomarkers for GTN.
妊娠滋养细胞疾病（GTD）包括一系列滋养细胞来源的疾病。最常见的 GTD 类型是葡萄胎（HM）。一些 HM 可以进一步发展为恶性妊娠滋养细胞肿瘤（GTN）。异常表达 microRNA（miRNA）被广泛报道参与癌症的发生和发展。miRNA 表达谱也已被证明是诊断、分期、预后和化疗反应的有用特征。到目前为止，GTD 进展过程中 miRNA 的特征尚未确定。在这项研究中，共收集了 34 例 GTN 和 60 例完全性 HM（CHM）滋养层组织。通过 miRNA 阵列筛选和 qRT-PCR 验证，发现 miR-370-3p、-371a-5p、-518a-3p、-519d-3p、-520a-3p 和 -934 等 6 种 miRNA 在 GTN 与 CHM 之间存在差异表达。功能分析进一步证明，miR-371a-5p 和 miR-518a-3p 促进绒癌细胞的增殖、迁移和侵袭。此外，我们证明 miR-371a-5p 与预测靶基因 BCCIP、SOX2 和 BNIP3L 的蛋白水平呈负相关，而 miR-518a-3p 与 MST1 和 EFNA4 呈负相关。我们首次证明 miR-371a-5p 和 miR-518a-3p 分别直接靶向 BCCIP 和 MST1 的 3'-UTR 区域。此外，我们发现 miR-371a-5p 和 miR-518a-3p 在绒癌细胞中调节与肿瘤发生和转移相关的多种途径。本研究结果可能为 GTD 的进展提供新的线索，并为 GTN 提供诊断生物标志物。
