Department of Thoracic Surgery, Esophagus and Mediastinum, Harbin Medical University Cancer Hospital, 150# Haping Road, Harbin, Heilongjiang, China.
Hum Cell. 2024 Jan;37(1):245-257. doi: 10.1007/s13577-023-01005-2. Epub 2023 Nov 23.
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.
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 中的作用及其涉及的潜在机制。通过分析公共人类癌症数据集，我们观察到食管癌细胞组织中 NUP93 的表达高于正常组织。通过慢病毒载体转导和嘌呤霉素选择稳定建立了 NUP93 过表达或敲低的 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，而过表达 NUP93 则显示出相反的效果。NUP93 正向调节 ESCC 细胞中的上皮-间充质转化和 AKT 信号转导。此外，NUP93 增加了 ESCC 细胞中程序性死亡配体 1（PD-L1）的表达，并减弱了 NK 细胞介导的 ESCC 细胞裂解。体内实验表明，NUP93 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。在机制上，我们证明了 E3 泛素蛋白连接酶 1（HECTD1）的 HECT 结构域有助于 NUP93 的泛素化和降解，并在 ESCC 中作为肿瘤抑制因子发挥作用。总之，本研究表明 NUP93 在 ESCC 中具有促肿瘤特性，并且 HECTD1 作为 ESCC 中 NUP93 的上游调节剂发挥作用。这些发现可能有助于研究 ESCC 中的潜在治疗靶点。
