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Review
. 2023 Sep 19;24(18):14301.
doi: 10.3390/ijms241814301.

Analysis of MicroRNA Signature Differentially Expressed in Pancreatic Islet Cells Treated with Pancreatic Cancer-Derived Exosomes

Young-Gon Kim  1 , Jisook Park  2 , Eun Young Park  2 , Sang-Mi Kim  1 , Soo-Youn Lee  1   3
Affiliations
Review

Analysis of MicroRNA Signature Differentially Expressed in Pancreatic Islet Cells Treated with Pancreatic Cancer-Derived Exosomes

Young-Gon Kim et al. Int J Mol Sci. .

Abstract

Since the majority of patients with pancreatic cancer (PC) develop insulin resistance and/or diabetes mellitus (DM) prior to PC diagnosis, PC-induced diabetes mellitus (PC-DM) has been a focus for a potential platform for PC detection. In previous studies, the PC-derived exosomes were shown to contain the mediators of PC-DM. In the present study, the response of normal pancreatic islet cells to the PC-derived exosomes was investigated to determine the potential biomarkers for PC-DM, and consequently, for PC. Specifically, changes in microRNA (miRNA) expression were evaluated. The miRNA specimens were prepared from the untreated islet cells as well as the islet cells treated with the PC-derived exosomes (from 50 patients) and the healthy-derived exosomes (from 50 individuals). The specimens were subjected to next-generation sequencing and bioinformatic analysis to determine the differentially expressed miRNAs (DEmiRNAs) only in the specimens treated with the PC-derived exosomes. Consequently, 24 candidate miRNA markers, including IRS1-modulating miRNAs such as hsa-miR-144-5p, hsa-miR-3148, and hsa-miR-3133, were proposed. The proposed miRNAs showed relevance to DM and/or insulin resistance in a literature review and pathway analysis, indicating a potential association with PC-DM. Due to the novel approach used in this study, additional evidence from future studies could corroborate the value of the miRNA markers discovered.

Keywords: diabetes mellitus; exosome; insulin resistance; miRNA; pancreatic cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Outline of experimental design. The miRNA specimens, Cancer, Healthy, and Control were prepared and DEmiRNA analysis was performed to determine miRNA markers differentially expressed from (A) Cancer. Acronyms: miRNA, microRNA; hIPCs, human pancreatic islet-derived precursor cells; DEmiRNA, differentially expressed miRNA.
Figure 2
Figure 2
Clustering pattern of normalized expression in three specimens: Cancer, Healthy, and Control. (A) Control and Healthy showed clustering based on the unsupervised clustering analysis. For visualization, 24 miRNA markers finally chosen in this study were used for heatmap construction. (B) In the two-dimensional scatter plot produced based on PCA analysis, Cancer and Healthy were located close and Cancer was distant from both Healthy and Control. In this analysis, all 2656 mature miRNA markers were used.
Figure 3
Figure 3
Volcano plots produced from DEmiRNA analysis. (A) DEmiRNA1 (Cancer vs. Control), and (B) DEmiRNA2 (Healthy vs. Control).
Figure 4
Figure 4
miRNA-gene network showing the interaction between candidate miRNAs and predicted target genes. The red nodes represent upregulated miRNAs and the blue nodes represent downregulated miRNAs. The green nodes represent predicted target genes. Acronyms: miRNA, microRNA.
Figure 5
Figure 5
KEGG pathways enriched by predicted target genes of candidate miRNA markers. In addition to the cancer-related pathways such as pathways in cancer, PC, and various signaling pathways, DM-related pathways such as insulin resistance, type 2 DM, PI3K-Akt signaling pathway, FoxO signaling pathway, and AGE-RAGE signaling pathways in diabetic complications showed higher significance. Acronyms: KEGG, Kyoto Encyclopedia of Genes and Genomes; miRNA, microRNA; PC, pancreatic cancer; DM, diabetes mellitus.
Figure 6
Figure 6
The miRNA-KEGG network showing the interaction between candidate miRNAs and KEGG pathways. The red nodes represent upregulated miRNAs and the blue nodes represent downregulated miRNAs. The green nodes represent KEGG pathways and larger green nodes represent KEGG pathways with degree >17. Acronyms: miRNA, microRNA; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 7
Figure 7
GO terms enriched by predicted target genes of candidate miRNA markers. Terms related to translation regulation showed higher significance. Acronyms: GO, gene ontology; miRNA, microRNA.
Figure 8
Figure 8
miRNA-GO network showing the interactions between candidate miRNAs and GO terms. The red nodes represent upregulated miRNAs and the blue nodes represent downregulated miRNAs. The green nodes represent GO terms and larger green nodes represent GO terms with degree > 12. Acronyms: miRNA, microRNA; GO, gene ontology.
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