Efp promotes in vitro and in vivo growth of endometrial cancer cells along with the activation of nuclear factor-κB signaling

Endometrial cancer is common among postmenopausal women and its incidence is increasing in developed countries. Considering that >80% of endometrial cancers are assumed to be estrogen-related, higher estrogen exposure will be relevant to tumorigenesis. Therefore, the roles of estrogen target genes will be important to understand the pathophysiological mechanisms. We previously revealed that estrogen-responsive RING finger protein Efp contributes to breast cancer progression through the protein degradation of cell cycle checkpoint 14-3-3σ. We and others also proposed that Efp has tumor-promoting activities in estrogen receptor (ER)-negative cancer cells. In addition, Efp plays a role in type I interferon production by activating antiviral signaling, which provokes nuclear factor-κB (NF-κB) signaling. In the present study, we investigate whether Efp plays a critical role in endometrial cancer biology. We show that siRNA-mediated Efp knockdown represses the proliferation and migration of endometrial cancer ER-positive Ishikawa and ER-negative HEC-1A cells. Efp knockdown increases 14-3-3σ protein levels and decreases the rates proliferative stage cells. Efp siRNA significantly inhibits the in vivo tumor growth of endometrial cancer cells in both subcutaneous and orthotopic xenograft models. Intriguingly, Efp knockdown represses NF-κB-dependent transactivation and transcription of target genes, such as IL6ST and IL18, in endometrial cancer cells. Overall, Efp would exert a tumor-promoting role through modulating NF-κB pathway and 14-3-3σ protein degradation in endometrial cancer regardless of its estrogen receptor status. Our results indicate that Efp could be a potential diagnostic and therapeutic target for endometrial cancer.

子宫内膜癌在绝经后女性中较为常见，且在发达国家的发病率呈上升趋势。据推测，超过80%的子宫内膜癌与雌激素相关，雌激素暴露水平升高与肿瘤发生密切相关，因此阐明雌激素靶基因的作用，对于理解子宫内膜癌的病理生理机制至关重要。本团队此前研究发现，雌激素应答性环指蛋白Efp可通过降解细胞周期检查点蛋白14-3-3σ，促进乳腺癌进展。本团队及其他学者还提出，Efp在雌激素受体（ER）阴性的癌细胞中具有促肿瘤活性。此外，Efp可通过激活抗病毒信号通路促进I型干扰素的产生，进而激活核因子-κB（NF-κB）信号通路。本研究旨在探究Efp在子宫内膜癌发生发展中的关键作用。研究发现，通过小干扰RNA（siRNA）介导的Efp敲低，可抑制雌激素受体阳性子宫内膜癌细胞系Ishikawa以及雌激素受体阴性子宫内膜癌细胞系HEC-1A的增殖与迁移能力。Efp敲低可上调14-3-3σ蛋白的表达水平，并降低子宫内膜癌细胞的增殖期细胞比例。在皮下异种移植瘤与原位异种移植瘤两种小鼠模型中，Efp siRNA均可显著抑制子宫内膜癌细胞的体内肿瘤生长。值得注意的是，在子宫内膜癌细胞中，Efp敲低可抑制NF-κB依赖的转录激活及其靶基因（如IL6ST、IL18）的转录水平。综上，无论子宫内膜癌细胞的雌激素受体状态如何，Efp均可通过调控NF-κB信号通路以及14-3-3σ蛋白的降解发挥促肿瘤作用。本研究结果表明，Efp有望成为子宫内膜癌潜在的诊断标志物与治疗靶点。