Integrated Analysis of Transcriptome Data Revealed AURKA and KIF20A as Critical Genes in Medulloblastoma Progression

Liang, Bo; Zhou, Yan; Jiao, Jiji; Xu, Lixia; Yan, Yan; Wu, Qiaoli; Tong, Xiaoguang; Yan, Hua

doi:10.3389/fonc.2022.875521

Cited by 13 publications

(4 citation statements)

References 62 publications

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“…Moreover, expression profiling of pediatric brain tumors has shown that AURKA was consistently and highly overexpressed (up to 106-fold) in tumor samples from all glioma grades and from patients varying from 4 months to 82 years old; however, mRNA expression showed only weak correlation with the Ki-67 labeling index, and significant associations with poor patient survival were only observed for GBM [ 530 ]. Overexpression of AURKA is also linked with survival in MB patients [ 531 ].…”

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

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Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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“…Animals were kept in the infrastructure of the Laboratory Animal Services Center (LASC), University of Zurich. 10…”

Section: Acknowledgmentsmentioning

confidence: 99%

“…AURKA controls centrosome maturation, bipolar spindle assembly, and cytokinesis, while AURKB and AURKC allow chromosome condensation, attachment to kinetochores and their alignment during metaphase and cytokinesis 9 . AURKA was identified as critical gene involved in MB progression 10 and AURKA inhibition in MB cell lines was found to increase chemosensitivity 11 . Exposure of SHH MB models to pan-AURK inhibitors were reported to enhance the sensitivity to conventional chemotherapies in vitro and in vivo 12 .…”

Section: Introductionmentioning

confidence: 99%

Repression of Aurora kinase B prevents growth and tissue invasion in medulloblastoma

Gries

Kumar

Kuttler

et al. 2023

Preprint

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Novel treatment strategies are required to overcome therapy-associated sequelae in survivors of pediatric medulloblastoma (MB) while maintaining therapeutic efficacy. The tissue impact on drug response in MB is not well understood and drug profiling in the physiological context of the tissue may reveal novel therapy targets. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with ex vivo organotypic cerebellum slice co-culture (OCSC), which allowed assessing tumor cell behavior in the tissue context. We screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) barasertib and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, Grp3 and Grp4 MB at nanomolar concentrations. We confirmed the necessity of AURKB for tumor growth through genetic suppression of AURKB by siRNA in the tissue context. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor dasatinib acts synergistically to repress tumor growth and invasiveness in the SHH MB cell model ONS76, but not in Grp3 MB cells. Finally, we demonstrate that pharmacological repression of AURKB in the tissue context is as effective as X-ray irradiation to repress tumor growth. Our data highlight that AURKBi is equally efficient as irradiation, suggesting that pharmacological targeting of AURKB may constitute a novel means to overcome radiotherapy limitations in patients younger than three years.

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“…[ 11 , 12 ] KIF20A is involved in regulation of microtubule bundle formation, midbody separation and cytokinesis. [ 13 ] Pathways associated with KIF20A include cell cycle, mitosis, and responses to cytosolic Ca2 + elevation. [ 14 ] Gene ontology (GO) annotations linked to KIF20A included protein kinase binding and ATP hydrolysis activities.…”

Section: Introductionmentioning

confidence: 99%

High expression of KIF20A in bladder cancer as a potential prognostic target for poor survival of renal cell carcinoma

Liu

Fan

et al. 2023

Medicine

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Urinary system tumors are malignant tumors, including renal cancer and bladder cancer. however, molecular target of them remains unclear. GSE14762 and GSE53757 were downloaded from GEO database to screen differentially expressed genes (DEGs). Weighted gene co-expression network analysis was performed. Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes were used for enrichment analysis. Gene ontology and Kyoto encyclopedia of genes and genomes analyses were performed on whole genome, as formulated by gene set enrichment analysis. Survival analysis was also performed. Comparative toxicogenomics database was used to identify diseases most associated with hub genes. A total of 1517 DEGs were identified. DEGs were mainly enriched in cancer pathway, HIF-1 signaling pathway, organic acid metabolism, glyoxylate and dicarboxylate metabolism, and protein homodimerization activity. Ten hub genes (TPX2, ASPM, NUSAP1, RAD51AP1, CCNA2, TTK, PBK, MELK, DTL, kinesin family member 20A [KIF20A]) were obtained, which were up-regulated in tumor tissue. The expression of KIF20A was related with the overall survival of renal and bladder cancer. KIF20A was up-regulated in the tumor tissue, and might worsen the overall survival of bladder and kidney cancer. KIF20A could be a novel biomarker of bladder and kidney cancer.

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Integrated Analysis of Transcriptome Data Revealed AURKA and KIF20A as Critical Genes in Medulloblastoma Progression

Cited by 13 publications

References 62 publications

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Repression of Aurora kinase B prevents growth and tissue invasion in medulloblastoma

High expression of KIF20A in bladder cancer as a potential prognostic target for poor survival of renal cell carcinoma

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