Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany.
Department of Pathology, Nordstadt Hospital Hannover, 30167 Hannover, Germany.
Int J Mol Sci. 2022 May 27;23(11):6037. doi: 10.3390/ijms23116037.
This study aimed to investigate the role of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) in glioblastoma (GBM) pathophysiology. To this end, PLOD2 protein expression was assessed by immunohistochemistry in two independent cohorts of patients with primary GBM (n1 = 204 and n2 = 203, respectively). Association with the outcome was tested by Kaplan−Meier, log-rank and multivariate Cox regression analysis in patients with confirmed IDH wild-type status. The biological effects and downstream mechanisms of PLOD2 were assessed in stable PLOD2 knock-down GBM cell lines. High levels of PLOD2 significantly associated with (p1 = 0.020; p2< 0.001; log-rank) and predicted (cohort 1: HR = 1.401, CI [95%] = 1.009−1.946, p1 = 0.044; cohort 2: HR = 1.493; CI [95%] = 1.042−2.140, p2 = 0.029; Cox regression) the poor overall survival of GBM patients. PLOD2 knock-down inhibited tumor proliferation, invasion and anchorage-independent growth. MT1-MMP, CD44, CD99, Catenin D1 and MMP2 were downstream of PLOD2 in GBM cells. GBM cells produced soluble factors via PLOD2, which subsequently induced neutrophils to acquire a pro-tumor phenotype characterized by prolonged survival and the release of MMP9. Importantly, GBM patients with synchronous high levels of PLOD2 and neutrophil infiltration had significantly worse overall survival (p < 0.001; log-rank) compared to the other groups of GBM patients. These findings indicate that PLOD2 promotes GBM progression and might be a useful therapeutic target in this type of cancer.
本研究旨在探讨赖氨酰氧化酶样蛋白 2（PLOD2）在胶质母细胞瘤（GBM）发病机制中的作用。为此，通过免疫组织化学法分别在两批原发性 GBM 患者中评估了 PLOD2 蛋白表达（n1=204，n2=203）。在 IDH 野生型状态得到证实的患者中，通过 Kaplan-Meier、对数秩和多变量 Cox 回归分析检验其与结局的相关性。在稳定敲低 PLOD2 的 GBM 细胞系中评估了 PLOD2 的生物学效应和下游机制。高水平的 PLOD2 与（p1=0.020；p2<0.001；对数秩）和预测（队列 1：HR=1.401，CI[95%]=1.009-1.946，p1=0.044；队列 2：HR=1.493；CI[95%]=1.042-2.140，p2=0.029；Cox 回归）GBM 患者的总体生存率差显著相关。PLOD2 敲低抑制肿瘤增殖、侵袭和非锚定依赖性生长。在 GBM 细胞中，MT1-MMP、CD44、CD99、Catenin D1 和 MMP2 是 PLOD2 的下游产物。GBM 细胞通过 PLOD2 产生可溶性因子，随后诱导中性粒细胞获得具有延长存活和释放 MMP9 特征的促肿瘤表型。重要的是，同时存在高水平 PLOD2 和中性粒细胞浸润的 GBM 患者的总体生存率明显差于其他 GBM 患者组（p<0.001；对数秩）。这些发现表明 PLOD2 促进 GBM 进展，可能是此类癌症的一个有用的治疗靶点。
