Expression Profiles of Circulating MicroRNAs in XELOX-Chemotherapy-Induced Peripheral Neuropathy in Patients with Advanced Gastric Cancer

Abstract

Gastric cancer (GC) is one of the most common cancers and a leading cause of cancer deaths around the world. Chemotherapy is one of the most effective treatments for cancer patients, and has remarkably enhanced survival rates. However, it has many side effects. Recently, microRNAs (miRNAs) have been intensively studied as potential biomarkers for cancer diagnosis and treatment monitoring. However, definitive biomarkers in chemotherapy-induced peripheral neuropathy (CIPN) are still lacking. The aim of this study was to identify the factors significant for neurological adverse events in GC patients receiving XELOX (oxaliplatin and capecitabine) chemotherapy. The results show that XELOX chemotherapy induces changes in the expression of hsa-miR-200c-3p, hsa-miR-885-5p, and hsa-miR-378f. Validation by qRT-PCR demonstrated that hsa-miR-378f was significantly downregulated in CIPN. Hsa-miR-378f was identified as showing a statistically significant correlation in GC patients receiving XELOX chemotherapy according to the analysis of differentially expressed (DE) miRNAs. Furthermore, 34 potential target genes were predicted using a web-based database for miRNA target prognostication and functional annotations. The identified genes are related to the peptidyl-serine phosphorylation and regulation of alternative mRNA splicing with enrichment in the gastric cancer, neurotrophin, MAPK, and AMPK signaling pathways. Collectively, these results provide information useful for developing promising strategies for the treatment of XELOX-chemotherapy-induced peripheral neuropathy.

Keywords: bioinformatics analysis; chemotherapy-induced peripheral neuropathy; gastric cancer; microRNAs.

Figure 1

Volcano plot and heatmap for the identification of DE miRNAs. (a) Volcano plot of DE miRNAs in plasma samples of GC patients who received fewer than 4 cycles and received 4–7 cycles of XELOX chemotherapy. Log2 fold changes between patients who received fewer than 4 cycles and received 4–7 cycles of XELOX chemotherapy are plotted on the x-axis, and the –log10 of the p-value is plotted on the y-axis. Red: upregulated miRNA; green: downregulated miRNA; (b) heatmap of miRNA expression data from plasma samples of GC patients who received fewer than 4 cycles and received 4–7 cycles of XELOX chemotherapy; red: upregulated miRNA; blue: downregulated miRNA.

Figure 2

The expression levels of three DE miRNAs in groups 1 and 2: (a) miR-200c-3p, (b) miR-378f, (c) miR-885-5p. Group 1: received fewer than 4 cycles of XELOX chemotherapy. Group 2: received 4–7 cycles of XELOX chemotherapy. ** represents p < 0.01.

Figure 3

The interaction network of DE miRNA and their experimentally validated target genes. The network was generated using the miRNet tool.

Figure 4

The gene ontology (GO) annotation analyses of the predicted target genes of the DE miRNAs. The top 10 most remarkably affected GO terms are listed along the y-axes. The x-axes denote fold enrichment. p < 0.05 was considered to indicate significant enrichment. The color and size of each dot denote –log10 (p-value). (a) The enrichment according to the biological process for the target genes of downregulated DE miRNAs, (b) the enrichment according to the cellular component for the target genes of downregulated DE miRNAs, (c) the enrichment according to the molecular function for the target genes of downregulated DE miRNAs.

Figure 5

The interaction network represents KEGG pathways and potential target genes. Enriched pathways were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

Figure 6

Overview of the analysis pipeline in this study.