The Molecular Signature Associated with Oxaliplatin-Induced Peripheral Neuropathy in Colorectal Cancer

Abstract

AbstractBackgroundOxaliplatin is the standard treatment option for colorectal cancer (CRC) which is one of the most prevalent forms of cancer. However, patients suffer either treatment discontinuation or adverse post-treatment life quality due to Oxaliplatin-induced peripheral neuropathy.MethodsOur study has comprehensively explored the molecular mechanisms underlying Oxaliplatin-induced peripheral neuropathy via an extensive literature survey and identified multiple genes that may contribute to neuropathy and neurotoxicity. In addition to that, the publicly available bulk transcriptomic data of Illumina HiSeq 2500 platform, comprising the CRC tissue of 18 individuals’ tumor and adjacent normal tissue was processed to identify differentially expressed genes (DEGs). Moreover, the single-cell RNA sequencing data of 10X genomics comprising normal and tumor tissues was subjected to analysis using Seurat and sctype R packages to uncover the cancer cells associated DEGs. Functional and pathway enrichment analysis was conducted using the Genecodis4 web-based tool. Next, RNA-seq data of CRC cell lines treated with Oxaliplatin compared with normal individuals, was also processed and DEGs were determined to validate the inhibition of a curated list of neuropathy-associated genes.ResultsFrom literature and database searches, a total of 1367 genes, including ion channel genes, normal sensory neuron-associated genes, and axon-excitability-related genes were collected that are either reported to be or may be contributing to neuropathy among cancer survivors upon oxaliplatin administration. The bulk transcriptomic data analysis revealed 715 DEGs and single-cell analysis uncovered 2,854 DEGs. Identified upregulated genes from single-cell data analysis, such as LGALS4, SPINK4, TFF3, REG4, and REG1A were found to be associated with tumor proliferation via epithelial-mesenchymal transitions, oxidative stress, dysregulated immune system, and inflammation which can be utilized as potential targets to devise novel therapeutic strategies for CRC treatment. Furthermore, many proteins involved in axon-excitability (NGF, SOD1, ROBO1, CNTNAP2, CNTNAP2, and KCNMB1), normal sensory neuron (SOX10, APOE, SST, S1PR1, and KCND3), voltage-gated sodium (SCNN1B, SCNN1G, SCNN1A, SCN1B, and SCN2B), calcium (CACNA2D2, CACNA1A, CACNA1C, CACNA1E, and CACNA1F), and potassium channels (KCND3, KCNMB1, KCNMA1, KCNJ2, and KCNN4) showed downregulation due to the oxaliplatin administration in CRC cell lines and their inhibition may have led to neuropathy which needs further validations.ConclusionOur study uncovers the downregulation of multiple genes upon oxaliplatin administration leading to neuropathy development and also elucidates potential therapeutic targets for better prognosis of CRC.