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.

The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival

“…In this study, we demonstrate LIN28B's essential role for Group 3 medulloblastoma cell proliferation and reveal the LIN28B-let-7-PBK axis as a major pathway exploited by these cancer cells. PBK was recently identified as a hub gene in medulloblastoma by Deng et al [15]. Here, we demonstrate that this stems from repression of let-7i due to overexpression of LIN28B.…”

“…PBK, a serine/ threonine kinase belonging to the mitogen-activated protein kinase kinase (MAPKK) family, is often overexpressed in cancers and is associated with poor prognosis [14]. More recently, PBK was identified as a hub gene in medulloblastoma by Deng et al [15].…”

The pivotal role of irradiation‐induced apoptosis in the pathogenesis and therapy of medulloblastoma

“…Furthermore, blockade of PKB decreased the proliferation as well as induced apoptosis in two MB cell lines in vitro (Figure 1). 27 Comparatively, the utmost proportion of apoptotic cells were detected 48 h post IR in both DAOY as well as D283MED cells with the apoptosis values three times greater in D283MED cells 38 . It is worth noting that elevated c‐MYC mRNA secretion, c‐MYC gene augmentation, as well as low‐level copy alterations of c‐MYC have been implicated as unfavorable prognosis factors for MB following IR (Figure 1).…”

“…Furthermore, abnormal MYC augmentation have been observed in about 17% of patients with group 3 MB and this reflects an essential feature of this subgroup 26 . Remarkably, the secretory level of protein kinase B (PKB) was apparently elevated in all MB subgroups compared to normal brain tissue, and elevated PKB secretion correlated with a poor prognosis in SHH, group 3 as well as group 4 MBs 27 …”

“…4 Notably, pharmacological blockade of PKB triggered a significate reduction in cell proliferation as well as augmented apoptosis, with the reduced phosphorylation of downstream effectors of PKB such as ERK1/2 and AKT in MB following IR via apoptosis. 27 Thus, these PKBs are potential therapeutic target in MB treatment via apoptosis.…”