Nucleoporin 93 (NUP93) is an important component of the nuclear pore complex, exhibiting pro-tumorigenic properties in some cancers. However, its function in esophageal squamous cell carcinoma (ESCC) has not been elucidated. This study aimed to investigate the effects of NUP93 in ESCC and the underlying mechanisms involved. Through analysis of public human cancer datasets, we observed higher expression of NUP93 in esophageal cancer tissues than in normal tissues. Stable ESCC cell lines with NUP93 overexpression or knockdown were established by lentiviral vector transduction and puromycin selection. NUP93 knockdown suppressed the proliferation, colony formation, cell cycle transition, migration, and invasion of ESCC cells, while the overexpression of NUP93 displayed opposite effects. NUP93 positively regulated epithelial–mesenchymal transition and AKT signaling transduction in ESCC cells. In addition, NUP93 increased the expression of programmed death ligand 1 (PD-L1) in ESCC cells and attenuated NK cell-mediated lysis of ESCC cells. In vivo experiments demonstrated that NUP93 promotes the growth of ESCC in nude mice, enhances Ki67 and PD-L1 expression, and promotes AKT signaling transduction in xenografts. Mechanistically, we demonstrated that the HECT domain E3 ubiquitin protein ligase 1 (HECTD1) contributes to the ubiquitination and degradation of NUP93 and acts as a tumor suppressor in ESCC. To conclude, this study has shown that NUP93 has pro-tumor properties in ESCC and that HECTD1 functions as an upstream regulator of NUP93 in ESCC. These findings may contribute to the investigation of potential therapeutic targets in ESCC.

Graphical abstract

中文翻译：

---

E3泛素蛋白连接酶HECTD1的新底物核孔蛋白93促进食管鳞状细胞癌进展

核孔蛋白 93 (NUP93) 是核孔复合体的重要组成部分，在某些癌症中表现出促肿瘤特性。然而，其在食管鳞状细胞癌（ESCC）中的功能尚未阐明。本研究旨在探讨 NUP93 在 ESCC 中的作用及其潜在机制。通过对公共人类癌症数据集的分析，我们观察到NUP93在食管癌组织中的表达量高于正常组织。通过慢病毒载体转导和嘌呤霉素选择建立了 NUP93 过表达或敲低的稳定 ESCC 细胞系。NUP93敲低抑制ESCC细胞的增殖、集落形成、细胞周期转变、迁移和侵袭，而NUP93过表达则表现出相反的作用。NUP93 正向调节 ESCC 细胞中的上皮-间质转化和 AKT 信号转导。此外，NUP93 增加 ESCC 细胞中程序性死亡配体 1 (PD-L1) 的表达，并减弱 NK 细胞介导的 ESCC 细胞裂解。体内实验表明，NUP93可促进裸鼠ESCC的生长，增强Ki67和PD-L1的表达，并促进异种移植物中的AKT信号转导。从机制上讲，我们证明了 HECT 结构域 E3 泛素蛋白连接酶 1 (HECTD1) 有助于 NUP93 的泛素化和降解，并在 ESCC 中充当肿瘤抑制因子。总之，本研究表明 NUP93 在 ESCC 中具有促肿瘤特性，并且 HECTD1 在 ESCC 中充当 NUP93 的上游调节因子。这些发现可能有助于食管鳞癌潜在治疗靶点的研究。

图形概要