WEE۱ Kinase Dysregulation in Glioblastoma: Insights into Cell Cycle Control and Post-Transcriptional Regulation through hsa-miR-۶۱۹-۵p and LINC۰۰۳۲۴

Brain cancer, particularly glioblastoma, represents one of the most aggressive forms of cancer. The G۲/M checkpoint in the cell cycle is a critical juncture for maintaining genomic stability, and WEE۱ kinase plays a vital role by inhibiting cyclin-dependent kinase ۱ (CDK۱), ensuring DNA repair before mitotic entry. Dysregulation of the WEE۱ gene has been linked to various cancers, including brain tumors, making it a potential therapeutic target. This study investigates the role of WEE۱ in brain cancer, using data from microarray analyses, signaling pathway interactions, and the impact of genetic variants. Methods: We performed a microarray analysis using the GEO dataset GSE۵۰۱۶۱, focusing on differential gene expression between brain cancer tissues and healthy samples. The pathway analysis was conducted using the Reactome database, where WEE۱ was found to interact with the G۲/M DNA Replication Checkpoint signaling pathway (R-HSA-۶۹۴۷۸), particularly with genes CCNB۱, CCNB۲, and CDK۱. Additionally, KEGG analysis identified CDK۱ as a key gene interacting with WEE۱ in the cell cycle pathway. A known coding single nucleotide polymorphism (SNP), rs۱۳۸۴۶۲۰۳۲, was examined, which causes an alanine-to-glycine substitution in WEE۱. The microRNA hsa-miR-۶۱۹-۵p, located in the ۳' UTR of WEE۱, was identified using the miRWalk database. Long non-coding RNA LINC۰۰۳۲۴ was also found to be associated with this miRNA. Finally, protein interaction analysis from the STRING database highlighted WEE۱’s strongest interaction with CDK۱, with the highest node count (۱۰). Results: Microarray analysis confirmed significant upregulation of WEE۱ expression in brain cancer tissues compared to healthy controls (logFC: ۵.۱۲۲, p-value < ۰.۰۰۱). Pathway enrichment via Reactome revealed that WEE۱ plays a central role in regulating the G۲/M DNA replication checkpoint, with critical interactions observed with CCNB۱, CCNB۲, and CDK۱. In particular, the interaction between WEE۱ and CDK۱ in the cell cycle pathway was the most prominent in the KEGG analysis. SNP rs۱۳۸۴۶۲۰۳۲, a non-synonymous variant, results in an alanine-to-glycine substitution, which may alter WEE۱'s regulatory function in cell cycle control. The miRNA hsa-miR-۶۱۹-۵p, interacting with WEE۱’s ۳' UTR, was identified as a potential post-transcriptional regulator of WEE۱ expression. Additionally, LINC۰۰۳۲۴ was found to interact with hsa-miR-۶۱۹-۵p, further indicating the complexity of WEE۱ regulation at the RNA level. The STRING database analysis corroborated these findings, showing a significant interaction between WEE۱ and CDK۱, which had the highest node score, underscoring the importance of their interaction in brain cancer cell proliferation. Conclusion: Our findings underscore the critical role of WEE۱ in brain cancer, particularly its involvement in the G۲/M checkpoint through its interactions with key cell cycle genes such as CDK۱, CCNB۱, and CCNB۲. Identifying the SNP rs۱۳۸۴۶۲۰۳۲ suggests a potential alteration in WEE۱’s functionality, contributing to the dysregulation of cell division in tumor cells. Furthermore, the interaction between WEE۱ and the miRNA hsa-miR-۶۱۹-۵p, as well as LINC۰۰۳۲۴, points to additional layers of regulatory complexity. The strong interaction between WEE۱ and CDK۱ highlights WEE۱’s potential as a therapeutic target in brain cancer, making it a promising biomarker for future therapeutic interventions.

کلیدواژه ها:

Brain Cancer ، Glioblastoma ، Microarray ، Bioinformatics