Abstract
Procollagen lysyl hydroxylase 1 (PLOD1) is highly expressed in malignant tumors such as esophageal squamous cell carcinoma, gastric cancer, and colorectal cancer. Bioinformatics analysis revealed that PLOD1 is associated with the progression of GBM, particularly the most malignant mesenchymal subtype (MES). Moreover, in the TCGA and CGGA datasets, the mean survival time of patients with high PLOD1 expression was significantly shorter than that of patients with low expression. The clinical samples confirmed this result. Therefore, we aimed to investigate the effect of PLOD1 on the development of mesenchymal GBM in vitro and in vivo and its possible mechanisms. Molecular experiments were conducted on the patient-derived glioma stem cells and found that PLOD1 expressed higher in tumor tissues and cancer cell lines of patients with GBM, especially in the MES. PLOD1 also enhanced tumor viability, proliferation, migration, and promoted MES transition while inhibited apoptosis. Tumor xenograft results also indicated that PLOD1 overexpression significantly promotes malignant behavior of tumors. Mechanistically, bioinformatics analysis further revealed that PLOD1 expression was closely associated with the NF-κB signaling pathway. Besides, we also found that hypoxic environments also enhanced the tumor-promoting effects of PLOD1. In conclusion, overexpression of PLOD1 may be an important factor in the enhanced invasiveness and MES transition of GBM. Thus, PLOD1 is a potential treatment target for mesenchymal GBM or even all GBM.
Highlights
Glioblastoma multiforme (GBM) is the most common primary brain malignancy with the worst prognosis
We showed that the level of PLOD1 expression was significantly higher in the mesenchymal subtype than in the proneural, neuronal, and classic subtype (Fig. 1d)
The results showed that enrichment of the mesenchymal subtype was present at high PLOD1 expression group, whereas enrichment of the proneural subtype was present at low PLOD1 expression group (Fig. 1e)
Summary
Glioblastoma multiforme (GBM) is the most common primary brain malignancy with the worst prognosis. Molecular subtyping has been regarded as a promising strategy to predict GBM evolution, common disease pathways, and rational treatment options [6]. Patients with MES GBM have the shortest median survival and the worst response to radiotherapy and chemotherapy [2, 7]. Studies have found that the natural course of lowgrade gliomas and GBM is often accompanied by MES transition during treatment, promoting tumor proliferation, invasion, and treatment tolerance [7,8,9]. A subpopulation of cells with stem cell-like properties, known as glioma initiating cells or glioma stem cells (GSCs), exists in GBM and plays the potential roles for multi-lineage differentiation and self-renewal that can lead to tumorigenesis, metastasis, Hypoxia-induced PLOD1 overexpression contributes to the malignant phenotype of glioblastoma via
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