Identification of PBK as a hub gene and potential therapeutic target for medulloblastoma.

Abstract

Medulloblastoma (MB) is the most frequent malignant brain tumor in pediatrics. Since the current standard of care for MB consisting of surgery, cranio-spinal irradiation and chemotherapy often leads to a high morbidity rate, a number of patients suffer from long-term sequelae following treatment. Targeted therapies hold the promise of being more effective and less toxic. Therefore, the present study aimed to identify hub genes with an upregulated expression in MB and to search for potential therapeutic targets from these genes. For this purpose, gene expression profile datasets were obtained from the Gene Expression Omnibus database and processed using R 3.6.0 software to screen differentially expressed genes (DEGs) between MB samples and normal brain tissues. A total of 282 upregulated and 436 downregulated DEGs were identified. Functional enrichment analysis revealed that the upregulated DEGs were predominantly enriched in the cell cycle, DNA replication and cell division. The top 10 hub genes were identified from the protein-protein interaction network of upregulated genes, and one identified hub gene [PDZ binding kinase (PBK)] was selected for further investigation due to its possible role in the pathogenesis of MB. The aberrant expression of PBK in MB was verified in additional independent gene expression datasets. Survival analysis demonstrated that a higher expression level of PBK was significantly associated with poorer clinical outcomes in non-Wingless MBs. Furthermore, targeting PBK with its inhibitor, HI-TOPK-032, impaired the proliferation and induced the apoptosis of two MB cell lines, with the diminished phosphorylation of downstream effectors of PBK, including ERK1/2 and Akt, and the activation of caspase-3. Hence, these results suggest that PBK may be a potential prognostic biomarker and a novel candidate of targeted therapy for MB.