CKS2 is overexpressed in high-grade and recurrent meningiomas and functions as an oncogene via the CKS2/miR-26a/miR-101 axis.

Abstract

Meningiomas are among the most common CNS tumors, typically benign (WHO grade 1) but with increasing malignancy in higher grades (2 and 3). Currently, there are no therapeutic alternatives for meningioma apart from surgery and radiotherapy. We performed multi-GEO dataset analyses to identify differentially expressed genes, pathways and ontologies, and hub genes within meningioma grades and/or recurrent tumors. Notably, cell cycle regulators (BUB1, CDK1, CCNB1, CCNB2, TOP2A, CKS2), kinesins (KIF11, KIF20A), and glutathione metabolism genes (GSTM1/3/5) were prominent. CKS2 was identified as a consistently upregulated gene in both higher-grade and recurrent tumors in multi-datasets and was selected for functional analyses. We first validated CKS2 expression in Indian meningioma patient cohort, demonstrating increased levels in higher grades. siRNA-mediated knockdown of CKS2 in meningioma cell line significantly reduced proliferation, colony formation, and migration, and altered cell cycle progression (notably G2-M transition). Univariate and multivariate cox survival analysis identified CKS2 as an independent prognostic factor for meningioma recurrence; its high expression correlated with shorter restricted mean survival time (RMST) to recurrence. ROC analysis revealed strong diagnostic potential of CKS2 in distinguishing high-grade and recurrent meningiomas. Further, epigenetic regulation of CKS2 via downregulated microRNAs-miR-26a-5p and miR-101-3p, and their tumor-suppressive effects in meningioma were elucidated. In summary, we identify the CKS2/miR-26a/miR-101 axis as a key regulatory axis in advanced grade meningiomas with therapeutic potential and highlight CKS2 as a promising diagnostic and prognostic marker.