PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer
PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer
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磷脂酶D_1通过NF-κB信号调节基质金属蛋白酶-13的表达促进膀胱癌侵袭
DOI：
10.1016/j.canlet.2021.04.014
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发表时间：
2021-05-03
期刊：
影响因子：
9.7
通讯作者：
Nishiyama, Hiroyuki
中科院分区：
文献类型：
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作者：
Nagumo, Yoshiyuki;Kandori, Shuya;Nishiyama, Hiroyuki
膀胱癌（BC）细胞从粘膜侵入肌肉层是BC进展的典型，而磷脂酶D同种型1（PLD 1）已知通过磷脂酸（PA）产生介导癌症的发展。因此，我们使用计算机模拟、体外和体内方法来详细说明PLD 1对BC侵袭的影响。在BC患者中，PLD1表达水平较高与预后较差相关。PLD1敲低显著抑制人BC细胞的细胞侵袭，观察到基质金属蛋白酶-13（MMP-13）介导这种作用。在我们的小鼠膀胱癌发生模型中，侵袭性BCs的发展被PLD 1敲除抑制，并且在该模型中的全局转录组学分析表明MMP-13是潜在的肿瘤侵袭基因，NF-κ B（核因子-κ B）是其转录调节因子。此外，PA给药增加MMP-13表达与NF-κ B p65磷酸化水平一致。总之，我们证明PLD 1通过NF-κ B信号通路调节MMP-13表达促进BC的肿瘤侵袭，并且PLD 1可能是预防BC患者临床进展的潜在治疗靶点。
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-kappa B (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-kappa B p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-kappa B signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients.