Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan.
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
Int J Mol Sci. 2024 May 20;25(10):5559. doi: 10.3390/ijms25105559.
Bladder cancer (BC) is a malignant tumor of the urinary system with high mortality and recurrence rates. Proteasome subunit type 4 (PSMB4) is highly expressed and has been identified as having oncogenic properties in a variety of cancer types. This study aimed to explore the effect of PSMB4 knockdown on the survival, migration, and angiogenesis of human bladder cancer cells with different degrees of malignancy. We analyzed the effects of PSMB4 knockdown in bladder cancer cells and endothelial cells in the tumor microenvironment. PSMB4 was highly expressed in patients with low- and high-grade urothelial carcinoma. Inhibition of PSMB4 reduced protein expression of focal adhesion kinase (FAK) and myosin light chain (MLC), leading to reduced migration. Furthermore, the suppression of PSMB4 decreased the levels of vascular endothelial factor B (VEGF-B), resulting in lower angiogenic abilities in human bladder cancer cells. PSMB4 inhibition affected the migratory ability of HUVECs and reduced VEGFR2 expression, consequently downregulating angiogenesis. In the metastatic animal model, PSMB4 knockdown reduced the relative volumes of lung tumors. Our findings suggest the role of PSMB4 as a potential target for therapeutic strategies against human bladder cancer.
膀胱癌（BC）是一种具有高死亡率和复发率的泌尿系统恶性肿瘤。蛋白酶体亚基类型 4（PSMB4）在多种癌症类型中表达高度上调，并被鉴定具有致癌特性。本研究旨在探讨 PSMB4 敲低对不同恶性程度的人膀胱癌细胞的生存、迁移和血管生成的影响。我们分析了 PSMB4 敲低在肿瘤微环境中的膀胱癌细胞和内皮细胞中的作用。PSMB4 在低级别和高级别尿路上皮癌患者中高表达。抑制 PSMB4 降低了黏着斑激酶（FAK）和肌球蛋白轻链（MLC）的蛋白表达，导致迁移减少。此外，PSMB4 的抑制降低了人膀胱癌细胞中血管内皮生长因子 B（VEGF-B）的水平，导致血管生成能力降低。PSMB4 抑制影响 HUVEC 的迁移能力并降低 VEGFR2 表达，从而下调血管生成。在转移动物模型中，PSMB4 敲低减少了肺肿瘤的相对体积。我们的研究结果表明 PSMB4 作为治疗人类膀胱癌的潜在靶点的作用。
