Identification of microRNA-Regulated Pathways through a Integration of Mcrorna-mRNA Microarray and Bioinformatics Analysis in CD34+ Cells of Myelodysplastic Syndromes

Abstract Background MicroRNAs (miRNAs) are considered to play a key role in the pathogenesis of myelodysplastic syndromes (MDS). However, the effect of miRNA and targeted mRNA on signal transduction is not fully understood in MDS. Objective The objective of this study is to identify the miRNAs-regulated pathways. Methods Affymetrix GeneChip microRNA and PrimeView Array were used to analyze miRNAs and gene expression profile of CD34+ cells in 12 MDS patients and 6 healthy controls. Comprehensive bioinformatics analysis of the coordinate expression of miRNAs and mRNAs including Difference, Go, Pathway, Pathway-network, miRNA-Gene-Network and miRNA-Go-Network analysis was performed to identify the miRNAs-regulated networks. Results 1. 34 differentially expressed miRNAs (5 up- and 29 down-regulated miRNAs) and 1783 mRNAs (405 up- and 1378 down-regulated mRNAs) in CD34+ cells from MDS and Healthy controls were identified by miRNA and mRNA microarray, respectively (Fig.1). 2. 25 dysregulated miRNAs and 234 targeted mRNAs were identified by a combination of Pearson's correlation analysis and prediction by TargetScan; 394 target relationship of miRNAs was established (Fig.2). 3. Go analysis revealed that these miRNA-mRNAs pairs were involved in signal transduction, apoptotic process, DNA-dependent transcription regulation, protein phosphophoration, etc. Pathway analysis showed that MAPK, JAK/STAT and PI3K/Akt signaling pathways might be regulated by these miRNA-mRNAs pairs (Fig.3). 4. The pathway-network analysis revealed that MAPK signaling pathway, Jak-Stat signaling pathway and apoptosis signaling pathway (displayed by red cycle) located in the downstream of signal networks (Fig. 3E). Dysregulation of These pathways may be more meaningful for explaining the pathogenesis of MDS. 5. Through a combination of Pathway, miRNA-Gene-Network and miRNA-Go- Network analysis, 29 miRNA-mRNA-regulated pathways were identified such as miR-148a/TEK/PI3K-Akt signaling pathway, miR-195/BDNF/MAPK signaling pathway, miR-195/DLL1/Notch signaling pathway, miR-145/CCND2/ JAK-STAT signaling pathway, etc. (Table 1). Conclusion Alteration expression of several miRNAs and targeted mRNAs might have an important impact on cancer-related cellular pathways including MAPK, PI3K/Akt, JAK/STAT, etc. The role of these miRNAs-mediated pathways in pathogenesis of MDS merit further investigation. Fig. 1 Affymetrix mcroRNA and mRNA microarray in MDS Fig. 1. Affymetrix mcroRNA and mRNA microarray in MDS Fig. 2 Significant miRNA-mRNA pairs identified through a integration of mcroRNA-mRNA microarray Fig. 2. Significant miRNA-mRNA pairs identified through a integration of mcroRNA-mRNA microarray Table 1. Parts of dysregulated miRNAs, genes and targeted pathway in MDS MicroRNA Style Gene_synbol Pathway miR-148a Down TEK PI3K-Akt signaling pathway ITGA9 PI3K-Akt signaling pathway KIT PI3K-Akt signaling pathway HMGA2 Transcriptional misregulation in cancer miR-145 Down HHEX Transcriptional misregulation in cancer MEIS1 Transcriptional misregulation in cancer miR-200c Down EFNA1 PI3K-Akt signaling pathway KLF3 Transcriptional misregulation in cancer miR-195 Up BDNF MAPK signaling pathway CDC25B MAPK signaling pathway DLL1 Notch signaling pathway MRAS MAPK signaling pathway miR-17 Up CAMK2D Calcium signaling pathway miR-19a Up MAML1 Notch signaling pathway SLC8A1 Calcium signaling pathway THBS1 Proteoglycans in cancer TNF MAPK signaling pathway TNFRSF1B Adipocytokine signaling pathway ACSL1 Adipocytokine signaling pathway EDNRB Calcium signaling pathway miR-19b Up CALM1 Calcium signaling pathway TNF Proteoglycans in cancer Fig. 3 Go and pathway analysis Fig. 3. Go and pathway analysis Disclosures No relevant conflicts of interest to declare.