Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea.
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, Korea.
Cell Death Dis. 2018 Nov 15;9(12):1138. doi: 10.1038/s41419-018-1186-5.
Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD3), a membrane-bound homodimeric enzyme, hydroxylates lysyl residues in collagen-like peptides; however, its role in lung cancer is unknown. This study aimed to investigate the role of PLOD3 as a pro-metastatic factor and to elucidate the underlying mechanism. First, we experimentally confirmed the release of PLOD3 in circulation in animal models, rendering it a potential serum biomarker for lung cancer in humans. Thereafter, we investigated the effects of PLOD3 overexpression and downregulation on cancer cell invasion and migration in vitro and in vivo, using human lung cancer cell lines and a mouse tumor xenograft model, respectively. Further, PLOD3 levels were determined in lung tissue samples from lung cancer patients. Functional analyses revealed that PLOD3 interacts with STAT3, thereby expressing matrix metalloproteinases (MMP-2 and MMP-9) and with urokinase plasminogen activator (uPA) to enhance tumor metastasis. PLOD3 and the STAT3 pathway were significantly correlated in the metastatic foci of lung cancer patients; PLOD3-STAT3 levels were highly correlated with a poor prognosis. These results indicate that PLOD3 promotes lung cancer metastasis in a RAS-MAP kinase pathway-independent manner. Therefore, secreted PLOD3 serves as a potent inducer of lung cancer metastasis and a potential therapeutic target to enhance survival in lung cancer.
赖氨酰氧化酶 3（PLOD3），一种膜结合的同源二聚体酶，羟化胶原蛋白样肽中的赖氨酰残基；然而，其在肺癌中的作用尚不清楚。本研究旨在探讨 PLOD3 作为促转移因子的作用，并阐明其潜在的机制。首先，我们在动物模型中实验证实了 PLOD3 在循环中的释放，使其成为人类肺癌潜在的血清生物标志物。此后，我们分别使用人肺癌细胞系和小鼠肿瘤异种移植模型，在体外和体内研究了 PLOD3 过表达和下调对癌细胞侵袭和迁移的影响。此外，还测定了肺癌患者肺组织样本中的 PLOD3 水平。功能分析表明，PLOD3 与 STAT3 相互作用，从而表达基质金属蛋白酶（MMP-2 和 MMP-9）和尿激酶纤溶酶原激活物（uPA），增强肿瘤转移。PLOD3 和 STAT3 通路在肺癌转移灶中显著相关；PLOD3-STAT3 水平与预后不良高度相关。这些结果表明，PLOD3 以 RAS-MAP 激酶通路非依赖性方式促进肺癌转移。因此，分泌的 PLOD3 可作为肺癌转移的有效诱导剂，也是增强肺癌患者生存的潜在治疗靶点。
