UPF1调控SOX2形成反馈环路影响子宫内膜癌干细胞生物学特征的机制

The mechanism for regulating the biological properties of ECSCs remains unclear, although it is known that RNA-binding proteins can regulate ECSCs properties. As shown by our early studies, UPF1 positively regulates SOX2 expression, binds to PVT1 as demonstrated through RIP-seq and RIP tests, miR-136(miR-508-5p) is predicted to bind with PVT1 and SOX2 through the same MRE, and the UPF1 promoter contains a putative SOX2 binding site. Given these findings, we sought to verify the following: UPF1 promotes PVT1 stability, PVT1 induces SOX2 to regulate ECSCs properties through ceRNA, and SOX2 positively regulates the feedback loop between UPF1 formation and ECSC function. The present study aims to determine the role of UPF1 in promoting PVT1 stability and regulating ECSC properties, to specify the role of PVT1 in ceRNA-mediated regulation of miR-136(miR-508-5p) for SOX2-mediated ECSC properties, and to confirm the role of SOX2 in regulating the aforementioned transcriptional feedback loop and, ultimately, ECSC function by confirming its binding with the putative SOX2 binding site in the UPF1 promote. This study also provides the new concepts and targets to more thoroughly describe ECSC functional mechanisms.

调控ECSCs生物学特性的机制尚不明确。RNA结合蛋白能调控ECSCs特性。课题组前期发现UPF1与SOX2表达正相关；通过RIP-seq和RIP实验证明UPF1结合PVT1；且预测到miR-136(miR-508-5p)分别以各自相同的MRE与PVT1和SOX2结合；UPF1启动子区存在与SOX2的结合位点。UPF1能否促进PVT1的稳定性；PVT1能否通过ceRNA机制诱导SOX2调控ECSCs特性；SOX2能否正性调控UPF1形成反馈环路，调控ECSCs特性呢？有待证明。本项目拟明确UPF1促进PVT1的稳定性调控ECSCs特性的作用；PVT1以ceRNA机制参与miR-136(miR-508-5p)调控SOX2介导的ECSCs干性的作用;通过确认SOX2与UPF1启动子关键位点结合调控转录形成反馈环路，调控ECSCs特性的机制。为深入研究ECSCs干性维持机制提供新思路和新靶点。

子宫内膜癌干细胞（endometrial cancer stem cells，ECSCs） 在子宫内膜癌 （endometrial cancer，EC） 转移、复发和化学抵抗中起着至关重要的作用。然而，维持ECSCs的分子机制仍然难以捉摸。在这里，我们发现UPF1和PVT1的表达在EC组织和ECSCs中上调，并与不良的临床病理特征相关。沉默UPF1或PVT1抑制了ECSCs恶性生物学行为以及自我更新、卡铂耐药性等干性特征。UPF1通过稳定PVT1来调节ECSCs的行为和命运。PVT1进一步与核心转录因子SOX2共享相同的miRNA响应元件，通过竞争性地“海绵化”miR-508-5p和miR-136，挽救了与miR-508-5p/miR-136特异性结合的SOX2，从而提高了SOX2的表达。而SOX2作为转录因子正向调控UPF1转录，从而对EC发挥促癌作用。我们证明了UPF1 /PVT1 /miR-508-5p、miR-136 /SOX2环路在调节ECSCs恶性生物学行为和细胞干性特征方面具有潜在价值，这为EC治疗提供了新的有希望的靶点。