Overexpression of PLOD3 promotes tumor progression and poor prognosis in gliomas

// Chia-Kuang Tsai 1, 2 , Li-Chun Huang 3 , Wen-Chiuan Tsai 4 , Shih-Ming Huang 1, 3 , Jiunn-Tay Lee 2 and Dueng-Yuan Hueng 1, 3, 5, 6 1 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC 2 Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 3 Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC 4 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 5 Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 6 Penghu Branch of Tri-Service General Hospital, Penghu, Taiwan, ROC Correspondence to: Dueng-Yuan Hueng, email: hondy2195@yahoo.com.tw Keywords: PLOD3; gene expression omnibus profile; glioma; prognosis Received: September 04, 2017      Accepted: February 21, 2018      Epub: February 28, 2018      Published: March 20, 2018 ABSTRACT High-grade gliomas are the most threatening brain tumors due to aggressive proliferation and poor prognosis. Thus, utilizing genetic glioma biomarkers to forecast prognosis and guide clinical management is crucial. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) modulates cancer progression and metastasis. However, its detailed function in cancer remains largely uninvestigated. PLOD3 expression was evaluated with real-time PCR in glioblastoma (GBM) cell lines and by Gene Expression Omnibus dataset analysis and immunohistochemistry of glioma tissues. We investigated the clinical use of PLOD3 for determining glioma prognosis. The biological roles of PLOD3 in proliferation, migration and invasion of GBM cells were studied both in vitro with wound-healing and transwell assays and in vivo using an orthotopic xenograft mouse model. Hypoxia and western blotting were applied to discover the molecular mechanisms underlying PLOD3 functions. PLOD3 mRNA and protein expression were upregulated in glioma tissues compared to normal brain tissues. PLOD3 overexpression was correlated with negative survival in glioma patients. PLOD3 silencing suppressed cell proliferation and induced G1 phase arrest through p53-independent regulation of the p21 pathway. Inhibition of PLOD3 in glioma cells decreased VEGF expression, migration and invasion by downregulating mesenchymal markers, including Snail and Twist. Notably, knockdown of PLOD3 inhibited HIF-1α accumulation via the ERK signaling pathway under hypoxia. Taken together, these discoveries reveal that PLOD3 is a potential therapeutic target in human gliomas.