Abstract
Poor prognosis of glioblastoma multiforme is strongly associated with the ability of tumor cells to invade the brain parenchyma, which is believed to be the major factor responsible for glioblastoma recurrence. Therefore, identifying the molecular mechanisms driving invasion may lead to the development of improved therapies for glioblastoma patients. Here, we investigated the role of procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2), an enzyme catalyzing collagen cross-linking, in the biology of glioblastoma invasion. PLOD2 mRNA was significantly overexpressed in glioblastoma compared to low-grade tumors based on the Oncomine datasets and REMBRANDT database for human gliomas. Kaplan-Meier estimates based on the TCGA dataset demonstrated that high PLOD2 expression was associated with poor prognosis. In vitro, hypoxia upregulated PLOD2 protein in U87 and U251 human glioma cell lines. siRNA knockdown of endogenous HIF-1α or treatment of cells with the HIF-1α inhibitor PX-478 largely abolished the hypoxia-mediated PLOD2 upregulation. Knockdown of PLOD2 in glioma cell lines led to decreases in migration and invasion under normoxia and hypoxia. In addition, levels of phosphorylated FAK (Tyr 397), an important kinase mediating cell adhesion, were reduced in U87-shPLOD2 and U251-shPLOD2 cells, particularly under hypoxic conditions. Finally, orthotopic U251-shPLOD2 xenografts were circumscribed rather than locally invasive. In conclusion, the results indicated that PLOD2 was a gene of clinical relevance with implications in glioblastoma invasion and treatment strategies.
Highlights
Glioblastoma multiforme (WHO grade IV) is the most common and fatal primary malignant tumor in the brain
To determine whether procollagenlysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was differentially expressed between glioblastoma and normal tissues, we broadly examined microarray data from patient samples within the Oncomine database
The invasive phenotype of glioblastoma is a major cause for poor prognosis in glioma patients [16]
Summary
Glioblastoma multiforme (WHO grade IV) is the most common and fatal primary malignant tumor in the brain. The diffuse infiltration of glioblastoma into the surrounding brain parenchyma makes complete resection of the tumor impossible and is believed to be the major factor responsible for the resistance of glioblastoma to treatment [1]. Investigation of molecular mechanisms driving tumor invasion is essential for the development of a curative therapy of the disease. To fully understand glioblastoma invasion requires some understanding of unique and complex tumor microenvironment as well as tumor cells. A hallmark characteristic of the glioblastoma microenvironment is hypoxia, which is associated with tumor growth, progression and resistance to conventional cancer therapies. Hypoxia prevents the degradation of hypoxiainducible factor (HIF)-1/2α, which dimerizes with www.impactjournals.com/oncotarget the constitutively active subunit, HIF-1β, to recruit transcriptional co-activators and initiate gene transcription [2]. How hypoxia regulates specific proteins involved in invasion might help in the development of new therapies
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