PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer

• Published in: Cancer letters Vol. 511; pp. 15 - 25
• Main Authors: Nagumo, Yoshiyuki, Kandori, Shuya, Tanuma, Kozaburo, Nitta, Satoshi, Chihara, Ichiro, Shiga, Masanobu, Hoshi, Akio, Negoro, Hiromitsu, Kojima, Takahiro, Mathis, Bryan J., Funakoshi, Yuji, Nishiyama, Hiroyuki
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28-07-2021; Elsevier Limited
• Subjects: Bladder cancer; Cancer; Carcinogenesis; Cell culture; Collagenase 3; Enzymes; Gene expression; Genomes; Invasiveness; Kidney cancer; Laboratories; Lipids; Matrix metalloprotease 13; Matrix metalloproteinase; Medical prognosis; Metalloproteinase; Metastasis; Mucosa; NF-κB protein; Phosphatidic acid; Phospholipase D; Phospholipase D1; Phosphorylation; Reagents; Signal transduction; Survival analysis; Tumor invasion; Tumors; United States > US; Japan; Matrix metalloprotease 13; Bladder cancer; Tumor invasion; Phospholipase D1; Phosphatidic acid
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.04.014

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.
•Elevated PLD1 expression is associated with poor prognosis in BC patients.•PLD1 promotes tumor invasion via PA–NF–kB-MMP-13 signaling pathway.•PLD1 might be a potential therapeutic target to prevent clinical BC progression.