Abstract：
Phospholipase D (PLD) lipid-signaling enzyme superfamily has been widely implicated in various human malignancies, but its role and underlying mechanism remain unclear in nasopharyngeal carcinoma (NPC). Here, we analyze the expressions of 6 PLD family members between 87 NPC and 10 control samples through transcriptome analysis. Our findings reveal a notable upregulation of PLD1 in both NPC tumors and cell lines, correlating with worse disease-free and overall survival in NPC patients. Functional assays further elucidate PLD1\'s oncogenic role, demonstrating its pivotal promotion of critical tumorigenic processes such as cell proliferation and migration in vitro, as well as tumor growth in vivo. Notably, our study uncovers a positive feedback loop between PLD1 and the NF-κB signaling pathway to render NPC progression. Specifically, PLD1 enhances NF-κB activity by facilitating the phosphorylation and nuclear translocation of RELA (p65), which in turn binds to the promoter of PLD1, augmenting its expression. Moreover, RELA overexpression markedly rescues the inhibitory effects in PLD1-depleted NPC cells. Importantly, the application of the PLD1 inhibitor, VU0155069, substantially inhibits NPC tumorigenesis in a patient-derived xenograft (PDX) model. Together, our findings identify PLD1/NF-κB signaling as a positive feedback loop with promising therapeutic and prognostic potential in NPC.
摘要：
磷脂酶D（PLD）脂质信号酶超家族已广泛涉及各种人类恶性肿瘤，但其在鼻咽癌（NPC）中的作用和潜在机制尚不清楚。这里,我们通过转录组分析分析了87例NPC和10例对照样品中6个PLD家族成员的表达。我们的发现揭示了在NPC肿瘤和细胞系中PLD1的显著上调。与鼻咽癌患者无病生存率和总生存率较差相关。功能测定进一步阐明了PLD1的致癌作用，证明了其对关键致瘤过程的关键促进，如体外细胞增殖和迁移，以及体内肿瘤的生长。值得注意的是,我们的研究揭示了PLD1和NF-κB信号通路之间的正反馈环,从而导致NPC进展.具体来说,PLD1通过促进RELA（p65）的磷酸化和核易位增强NF-κB活性，它又与PLD1的启动子结合，增强其表达。此外，RELA过表达显着挽救了PLD1耗尽的NPC细胞中的抑制作用。重要的是,PLD1抑制剂的应用，VU0155069在患者来源的异种移植模型中显著抑制NPC肿瘤发生。一起,我们的发现将PLD1/NF-κB信号传导作为一个正反馈回路,在NPC中具有良好的治疗和预后潜力.
