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Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
Identification of RPA3 as a Potential Functional Effector of Chromosome 7 Gain in Glioblastoma
Yulu Ge1,2, Zhan Hu2, Wenbo Wu1
1Department of Neurosurgery, Center for Malignant Brain Tumors, National Glioma MDT Alliance, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Abstract:
Background: Chromosome 7 gain (chr7 gain) is a highly prevalent early event in glioblastoma (GBM). Because chr7 gain usually involves broad chromosomal amplification, its biological impact is unlikely to be fully explained by canonical loci such as EGFR and MET. The contribution of less-characterized, dosage-sensitive genes on chromosome 7 remains insufficiently defined. This study aimed to identify additional chr7 candidates associated with malignant phenotypes in GBM. Methods: Transcriptomic, copy-number, and clinical data from TCGA-GBM and TCGA-LGG were analyzed to characterize chr7-gain-associated alterations and prioritize candidate genes. Refined GBM and histologic GBM cohorts based on the WHO 2021 framework were used for candidate selection. RPA3-associated pathway features were examined using ssGSEA, PROGENy, WGCNA, and protein-protein interaction analysis, with external validation in the CGGA-693 cohort. Single-cell RNA-seq analysis compared chr7-gain and chr7-normal-copy tumor subclusters. Functional relevance was evaluated by siRNA-mediated knockdown in U87 and U118 cells. Results: Chr7 gain was enriched in high-grade IDH-wildtype gliomas and was associated with cell-cycle- and DNA repair-related programs. RPA3 was prioritized as a dosage-sensitive chromosome 7 candidate based on its upregulation in chr7-gain tumors, association with poor prognosis, and concordance with replication- and repair-related signatures. In vitro, RPA3 knockdown impaired cell growth, proliferation, colony formation, and migration. Single-cell analysis suggested greater transcriptomic and network-level relevance of RPA3 in chr7-gain tumor cells. Conclusions:RPA3 is a dosage-sensitive chromosome 7 candidate associated with aggressive and replication-/repair-related phenotypes in GBM. Increased RPA3 expression may contribute to the selective advantage associated with chr7 gain, which supports further investigation as potential therapeutic target.
