Weighted gene co-expression network-based approach to identify key genes associated with anthracycline-induced cardiotoxicity and construction of miRNA-transcription factor-gene regulatory network

Abstract

Background Cardiotoxicity is a common complication following anthracycline chemotherapy and represents one of the serious adverse reactions affecting life, which severely limits the effective use of anthracyclines in cancer therapy. Although some genes have been investigated by individual studies, the comprehensive analysis of key genes and molecular regulatory network in anthracyclines-induced cardiotoxicity (AIC) is lacking but urgently needed. Methods The present study integrating several transcription profiling datasets aimed to identify key genes associated with AIC by weighted correlation network analysis (WGCNA) and differentially expressed analysis (DEA) and also constructed miRNA-transcription factor-gene regulatory network. A total of three transcription profiling datasets involving 47 samples comprising 41 rat heart tissues and 6 human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) samples were enrolled. Results The WGCNA and DEA with E-MTAB-1168 identified 14 common genes affected by doxorubicin administrated by 4 weeks or 6 weeks. Functional and signal enrichment analyses revealed that these genes were mainly enriched in the regulation of heart contraction, muscle contraction, heart process, and oxytocin signaling pathway. Ten (Ryr2, Casq1, Fcgr2b, Postn, Tceal5, Ccn2, Tnfrsf12a, Mybpc2, Ankrd23, Scn3b) of the 14 genes were verified by another gene expression profile GSE154603. Importantly, three key genes (Ryr2, Tnfrsf12a, Scn3b) were further validated in a hiPSCMs-based in-vitro model. Additionally, the miRNA-transcription factor-gene regulatory revealed several top-ranked transcription factors including Tcf12, Ctcf, Spdef, Ebf1, Sp1, Rcor1 and miRNAs including miR-124-3p, miR-195-5p, miR-146a-5p, miR-17-5p, miR-15b-5p, miR-424-5p which may be involved in the regulation of genes associated with AIC. Conclusions Collectively, the current study suggested the important role of the key genes, oxytocin signaling pathway, and the miRNA-transcription factor-gene regulatory network in elucidating the molecular mechanism of AIC.

Current Status and Trends of Research on Anthracycline-Induced Cardiotoxicity from 2002 to 2021: A Twenty-Year Bibliometric and Visualization Analysis

“…To date, multiple genes and intergenic variants have now emerged as risk loci for ACT, including the solute carrier family 22 member 7 (SLC22A7), the ATP binding cassette subfamily C member 1 (ABCC1), the carbonyl reductase 3 (CBR3), the neutrophil cytosolic factor 4 (NCF4), and transient receptor potential cation channel subunit 6 (TRPC6) [ 114 , 115 ]. Recently, a gene regulatory network has been constructed and further screened several key ones among identified genes, including the ryanodine receptor 2 (RYR2), the tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), and the sodium voltage-gated channel beta subunit 3 (SCN3B) [ 116 ].…”

TCEAL5 cooperates with the NuRD complex to epigenetically silence mesenchymal genes in glioma

“…Compared to other TCEAL family members, TCEAL5 remains a relatively understudied member of the TCEAL gene family. While scarce, emerging evidence suggests TCEAL5's roles in cellular proliferation, cardiac health, and muscle cell differentiation [10][11][12][13] . In the present study, we report that TCEAL5 expression is decreased in glioma and forced expression of TCEAL5 inhibits cell migration and invasion.…”

MicroRNA composition of plasma extracellular vesicles: a harbinger of late cardiotoxicity of doxorubicin

“…However, knowledge on long-term transcriptomic processes leading to health complications due to anthracycline use is very limited, despite constantly increasing number of cancer survivors (Miller et al 2019 ). Furthermore, the analysis of gene expression in cardiac tissues is not feasible in human subjects, thus studies on molecular aspects of doxorubicin action are mostly limited to cultured cardiomyocytes in a short time scale or to animals (Wan et al 2021 ).…”