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Updated: Oct 14, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Weighted gene co-expression network-based approach to identify key genes associated with anthracycline-induced
Guoxing Wan1, Peinan Chen2, Xue Sun1
1Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Road, Shiyan, 442000, Hubei, China.
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.
Insights
This study identifies key genes and regulatory networks involved in anthracyclines-induced cardiotoxicity (AIC). Findings highlight the role of specific genes and pathways in understanding and potentially treating this serious chemotherapy side effect.
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
Background:
- Anthracycline chemotherapy can cause life-threatening cardiotoxicity, limiting its use in cancer treatment.
- A comprehensive understanding of the molecular mechanisms underlying anthracyclines-induced cardiotoxicity (AIC) is lacking.
- Identifying key genes and regulatory networks is crucial for managing AIC.
Purpose of the Study:
- To identify key genes associated with AIC using integrated transcription profiling datasets.
- To construct a miRNA-transcription factor-gene regulatory network for AIC.
- To elucidate the molecular mechanisms of AIC.
Main Methods:
- Weighted correlation network analysis (WGCNA) and differentially expressed analysis (DEA) were performed on gene expression datasets.
- Data from rat heart tissues and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) were analyzed.
- A miRNA-transcription factor-gene regulatory network was constructed.
Main Results:
- 14 common genes affected by doxorubicin were identified, enriched in heart contraction and oxytocin signaling pathways.
- Ten of these genes were validated in an independent dataset.
- Three key genes (Ryr2, Tnfrsf12a, Scn3b) were validated in an in-vitro hiPSCMs model.
- A regulatory network involving specific transcription factors and miRNAs was proposed.
Conclusions:
- Key genes, the oxytocin signaling pathway, and the miRNA-transcription factor-gene regulatory network play significant roles in AIC.
- These findings provide insights into the molecular mechanisms of AIC.
- This research may aid in developing strategies to mitigate cardiotoxicity from anthracycline chemotherapy.
