Increasing evidences have shown that pregnant women might miscarry after exposure with environmental BaP (benzo(a)pyrene). Additionally, BPDE (benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide), the ultimate metabolite of BaP, could induce dysfunctions of human trophoblast cells. However, it is rarely correlated between miscarriage and trophoblast dysfunctions. Moreover, their underlying mechanisms are still largely unidentified. In this study, a novel lncRNA (long non-coding RNA), lnc-HZ08, was identified to be highly expressed in human recurrent miscarriage (RM) tissues and in BPDE-treated human trophoblast cells. Lnc-HZ08 acts as a RNA scaffold to interact with both PI3K and its ubiquitin ligase CBL (Cbl proto-oncogene), enhances their protein interactions, and promotes PI3K ubiquitin degradation. In RM tissues and BPDE-treated trophoblast cells, DNA methylation level in lnc-HZ08 promoter region was reduced, which promotes estrogen receptor 1 (ER)–mediated lnc-HZ08 transcription. Subsequently, this upregulated lnc-HZ08 downregulated PI3K level, suppressed PI3K/p-AKT/p-P21/CDK2 pathway, and thus weakened proliferation, migration, and invasion of human trophoblast cells, which further induces miscarriage. These results may provide novel scientific and clinical insights in the occurrence of unexplained miscarriage.

Graphical abstract

中文翻译：

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Lnc-HZ08 通过促进 PI3K 泛素降解来调节 BPDE 诱导的滋养层细胞功能障碍，并与流产有关

越来越多的证据表明，孕妇在接触环境中的 BaP（苯并（a）芘）后可能会流产。此外，BaP 的最终代谢物 BPDE（benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide）可诱导人滋养层细胞功能障碍。然而，流产和滋养层功能障碍之间很少相关。此外，它们的潜在机制仍然很大程度上未知。在这项研究中，一种新的 lncRNA（长链非编码 RNA）lnc-HZ08 被鉴定为在人类复发性流产 (RM) 组织和 BPDE 处理的人类滋养层细胞中高度表达。Lnc-HZ08 作为 RNA 支架与 PI3K 及其泛素连接酶 CBL（Cbl 原癌基因）相互作用，增强它们的蛋白质相互作用，并促进 PI3K 泛素降解。在 RM 组织和 BPDE 处理的滋养层细胞中，lnc-HZ08 启动子区域的 DNA 甲基化水平降低，从而促进雌激素受体 1 (ER) 介导的 lnc-HZ08 转录。随后，这种上调的lnc-HZ08下调PI3K水平，抑制PI3K/p-AKT/p-P21/CDK2通路，从而削弱人滋养层细胞的增殖、迁移和侵袭，进一步诱导流产。这些结果可能为不明原因流产的发生提供新的科学和临床见解。

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