Department of Urology, The Sixth Affiliated Hospital of Wenzhou Medical University (The People's Hospital of Lishui), Lishui, Zhejiang, China.
Environ Toxicol. 2023 Jul;38(7):1678-1689. doi: 10.1002/tox.23796. Epub 2023 Apr 23.
This study identified the function of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) on bladder cancer (BLCA).
NEDD4L expression in BLCA patients was scrutinized. The function of NEDD4L on the viability, apoptosis, migration and invasion of BLCA cells was evaluated by cell counting kit-8, flow cytometry and Transwell assays. The effect of NEDD4L on the cisplatin (DDP) resistance of the DDP-resistant BLCA cells was explored. The influence of NEDD4L on the p62/Keap1/Nrf2 pathway activity in BLCA cells was tested by Western blot. Rescue experiments were implemented to verify whether NEDD4L regulated BLCA cell malignant behavior by mediating the Keap1/Nrf2 pathway activity via p62. The effect of NEDD4L on the growth and the p62/Keap1/Nrf2 pathway activity in vivo was researched in xenograft tumor nude mice models.
The down-regulated NEDD4L in BLCA patients was associated with unfavorable survival. NEDD4L suppressed the viability (inhibition rate 57.1%/49.0%), migration (inhibition rate 49.7%/77.1%), invasion (inhibition rate 50.6%/75.7%), promoted the apoptosis of T24/5637 cells (promotion rate 243.8%/201.9%), reduced IC 50 of DDP-resistant T24/5637 cells from 132.2/101.8 to 57.81/59.71 μM, respectively, and inactivated the p62/Keap1/Nrf2 pathway in T24/5637 cells. p62 up-regulation partially abrogated the inhibition of NEDD4L on the Keap1/Nrf2 pathway activity, the malignant behavior of BLCA cells, and the DDP resistance of DDP-resistant BLCA cells. NEDD4L overexpression inhibited the tumor growth and the p62/Keap1/Nrf2 pathway activity in vivo in BLCA.
NEDD4L inhibits the progression of BLCA by inactivating the p62/Keap1/Nrf2 pathway. It may be an effective target for BLCA treatment.
本研究旨在探讨神经前体细胞表达发育下调因子 4 样蛋白（NEDD4L）在膀胱癌（BLCA）中的作用。
检测 BLCA 患者中 NEDD4L 的表达。通过细胞计数试剂盒-8 检测、流式细胞术和 Transwell 检测评估 NEDD4L 对 BLCA 细胞活力、凋亡、迁移和侵袭的影响。探讨 NEDD4L 对顺铂（DDP）耐药 BLCA 细胞耐药性的影响。通过 Western blot 检测 NEDD4L 对 BLCA 细胞中 p62/Keap1/Nrf2 通路活性的影响。通过 p62 介导的 Keap1/Nrf2 通路活性，进行挽救实验以验证 NEDD4L 是否通过调节 BLCA 细胞恶性行为。在裸鼠异种移植肿瘤模型中研究 NEDD4L 对体内肿瘤生长和 p62/Keap1/Nrf2 通路活性的影响。
BLCA 患者中下调的 NEDD4L 与不良预后相关。NEDD4L 抑制 T24/5637 细胞活力（抑制率 57.1%/49.0%）、迁移（抑制率 49.7%/77.1%）、侵袭（抑制率 50.6%/75.7%）、促进细胞凋亡（促进率 243.8%/201.9%），降低 DDP 耐药 T24/5637 细胞的 IC50 值，分别从 132.2/101.8 降至 57.81/59.71 μM，同时抑制 T24/5637 细胞中 p62/Keap1/Nrf2 通路活性。p62 上调部分削弱了 NEDD4L 对 Keap1/Nrf2 通路活性、BLCA 细胞恶性行为和 DDP 耐药性的抑制作用。NEDD4L 过表达抑制体内 BLCA 肿瘤生长和 p62/Keap1/Nrf2 通路活性。
NEDD4L 通过失活 p62/Keap1/Nrf2 通路抑制 BLCA 的进展。它可能是 BLCA 治疗的有效靶点。
