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MRNA expression profiles of human iPSC-derived sensory neurons treated with paclitaxel, vincristine, bortezomib or cisplatin in the presence and absence of SP600125

ABSTRACT: For our investigation of the role of c-Jun in the underlying mechanisms of chemotherapy-induced peripheral neuropathy (CIPN), human iPSCs derived from patients were differentiated into sensory neurons and subsequently treated in vitro with four different chemotherapeutic drugs (paclitaxel, vincristine, bortezomib or cisplatin) in the presence and absence of small molecule inhibitor, SP600125. The transcriptomic analyses of such treated samples revealed upregulated transcription of c-Jun mRNA across the four drug types, which was reduced upon addition of SP600125. While this suggests the involvement of the JNK signalling pathway, detailed analyses of correlation coefficient revealed that a high correlation of c-Jun with neuronal injury, neuroinflammatory, metabolic and neuromodulation markers, thus identifying a central role of c-Jun in CIPN pathophysiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305998 | GEO | 2025/10/01

REPOSITORIES: GEO

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Gene expression signatures of chemotherapy-induced neuropathy induced by vincristine

Project description:Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of several cancer types. However, a main side-effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to decreased quality of life, changes in chemotherapeutic treatment or even treatment cessation. Although painful symptoms associated with CIPN are faithfully recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in peripheral sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia isolated from mice treated with vincristine, oxaliplatin, and cisplatin with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq using 75-nucleotide single end runs revealed 368, 295 and 256 differential expressed genes (DEGs) induced by treatment with vincristine, oxaliplatin and cisplatin, respectively. Although there were many similarities in DEGs between chemotherapeutic agents, only 5 genes were dysregulated in all groups. Cell type enrichment analysis (CTEA) and gene set enrichment analysis (GSEA) showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed inflammatory and neuropathic gene expression signature. Only ‘regulation of transport’ and ‘response to external stimuli’ were gene ontology terms shared between all treatments. These results provide insight into the recruitment of innate and adaptive immune responses to DRG tissue and indicate enhanced neuro-inflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.

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