Department of Urology, Faculty of Medicine and Graduate School of Comprehensive Human Science, University of Tsukuba, Ibaraki, Japan.
Department of Urology, Faculty of Medicine and Graduate School of Comprehensive Human Science, University of Tsukuba, Ibaraki, Japan.
Cancer Lett. 2021 Jul 28;511:15-25. doi: 10.1016/j.canlet.2021.04.014. Epub 2021 May 1.
Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognoses. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to mediate this effect. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-κB (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-κB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-κB signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients.
膀胱癌（BC）细胞从黏膜侵入肌肉层的侵袭是 BC 进展的典型特征，而磷脂酶 D 同工酶 1（PLD1）通过产生磷酸脂酸（PA）已知可介导癌症的发展。因此，我们使用了计算机模拟、体外和体内方法来详细研究 PLD1 对 BC 侵袭的影响。在 BC 患者中，PLD1 表达水平较高与预后不良相关。PLD1 敲低显著抑制了人 BC 细胞的细胞侵袭，并且观察到基质金属蛋白酶-13（MMP-13）介导了这种作用。在我们的小鼠膀胱癌发生模型中，PLD1 敲除抑制了侵袭性 BC 的发展，并且该模型中的全局转录组分析表明 MMP-13 是一种潜在的肿瘤侵袭基因，核因子-κB（NF-κB）是其转录调节剂。此外，PA 给药增加了与 NF-κB p65 磷酸化水平一致的 MMP-13 表达。总之，我们证明了 PLD1 通过 NF-κB 信号通路调节 MMP-13 表达促进 BC 的肿瘤侵袭，并且 PLD1 可能是预防 BC 患者临床进展的潜在治疗靶点。
