Fan Li, Zhou Yulin, Liu Shouyong, Zhuo Xinfeng, Qu Le, Wu Ding, Wang Suchun, Pan Xin, Zhao Tangliang, Xu Feng, Ge Jingping, Zhou Wenquan
Department of Urology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
Outpatient Department, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
Cancer Biol Ther. 2025 Dec;26(1):2535774. doi: 10.1080/15384047.2025.2535774. Epub 2025 Aug 5.
Bladder cancer (BLCA) is a common urinary malignancy with high metastatic potential. However, the mechanisms underlying its progression remain unclear. This study aimed to investigate the role and regulatory mechanisms of NR4A3, a nuclear receptor involved in apoptosis and tumor suppression, in BLCA progression, particularly its impact on anoikis resistance and metastasis. NR4A3 expression levels were analyzed using the GEPIA database. Functional studies were conducted by overexpressing NR4A3 in adherent and suspension-cultured BLCA cells. Apoptosis, invasion, migration, and ER stress marker (Bip and CHOP) expression were evaluated. Subcutaneous and lung metastasis models in BALB/c nude mice were used for in vivo validation. GEPIA analysis showed that NR4A3 is significantly downregulated in BLCA. NR4A3 overexpression increased apoptosis, reduced invasion and migration, and upregulated Bip and CHOP expression. , NR4A3 overexpression significantly reduced lung metastasis in BALB/c nude mice ( = 8 per group, < .001). Mechanistically, NR4A3 promoted ER stress by regulating the EWSR1/Ezrin pathway, thereby suppressing anoikis resistance. NR4A3 functions as a tumor suppressor in BLCA by enhancing endoplasmic reticulum stress and inhibiting anoikis resistance through the EWSR1/Ezrin pathway. It may serve as a promising therapeutic target for metastatic BLCA.
膀胱癌（BLCA）是一种具有高转移潜能的常见泌尿系统恶性肿瘤。然而，其进展的潜在机制仍不清楚。本研究旨在探讨参与细胞凋亡和肿瘤抑制的核受体NR4A3在BLCA进展中的作用和调控机制，特别是其对失巢凋亡抗性和转移的影响。使用GEPIA数据库分析NR4A3表达水平。通过在贴壁培养和悬浮培养的BLCA细胞中过表达NR4A3进行功能研究。评估细胞凋亡、侵袭、迁移和内质网应激标志物（Bip和CHOP）的表达。使用BALB/c裸鼠的皮下和肺转移模型进行体内验证。GEPIA分析显示，NR4A3在BLCA中显著下调。NR4A3过表达增加细胞凋亡，减少侵袭和迁移，并上调Bip和CHOP表达。此外，NR4A3过表达显著减少BALB/c裸鼠的肺转移（每组8只，<0.001）。机制上，NR4A3通过调节EWSR1/埃兹蛋白途径促进内质网应激，从而抑制失巢凋亡抗性。NR4A3通过增强内质网应激并通过EWSR1/埃兹蛋白途径抑制失巢凋亡抗性，在BLCA中发挥肿瘤抑制作用。它可能是转移性BLCA的一个有前景的治疗靶点。
