Exploring the potential molecular mechanism of trastuzumab-induced cardiotoxicity based on RNA sequencing and
Huan Hou1, Ying Xu2, Meilin Xie3
1Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
Abstract:
The cardiotoxicity of trastuzumab (TRZ) seriously affects the prognosis of breast cancer patients, but the underlying mechanisms remains to be elucidated. This study aimed to investigate the potential molecular mechanisms of TRZ-induced cardiotoxicity based on RNA sequencing (RNA-Seq) and bioinformatics analysis. Kunming mice were exposed to 10 mg/kg TRZ for 6 and 10 days, followed by echocardiography, histopathology and serum biochemical analysis to evaluate the cardiotoxicity model. The results showed no significant changes after 6 days administration of TRZ. After 10 days administration of TRZ, the mice showed cardiac dysfunction, myocardial injury and fibrosis, and the serum levels of LDH, CK, CK-MB and cTnI were increased compared to the control [CON (Day 10)] group, indicating the cardiotoxicity model was successfully established. We compared gene expression levels in mice cardiac tissues by RNA-Seq and screened out 593 differentially expressed genes (DEGs). Results based on Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network analysis and RT-PCR revealed that the CD74/STAT1 signaling pathway might play an important role in TRZ-induced cardiotoxicity. In the TRZ group, the protein expressions of CD74, p-STAT1 (Tyr) and p-STAT1 (Ser) were increased. The TUNEL staining showed increased apoptosis of cardiomyocytes. In addition, an increased expressions of Bax, Caspase-3, IFN-γ and TNF-α and a decreased expression of Bcl-2 were observed in Western blot results, indicating the apoptosis and inflammation levels were increased. These findings suggested that TRZ may induce cardiotoxicity in mice by activating the CD74/STAT1 signaling pathway, which might be related to the induction of apoptosis and inflammation.
Insights
Trastuzumab (TRZ) cardiotoxicity in breast cancer patients may stem from the CD74/STAT1 pathway, leading to apoptosis and inflammation. This study identified key molecular mechanisms in a mouse model, offering insights for improved patient outcomes.
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
Background:
- Trastuzumab (TRZ) is a critical therapy for HER2-positive breast cancer.
- TRZ-induced cardiotoxicity significantly impacts patient prognosis.
- The precise molecular mechanisms underlying TRZ cardiotoxicity remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms of trastuzumab-induced cardiotoxicity using RNA sequencing and bioinformatics.
- To establish and validate a mouse model for studying TRZ cardiotoxicity.
Main Methods:
- Kunming mice were treated with TRZ (10 mg/kg) for 6 and 10 days.
- Cardiotoxicity was assessed via echocardiography, histopathology, and serum biochemical analysis.
- RNA sequencing, Gene Ontology, KEGG pathway, and protein-protein interaction network analyses were performed on cardiac tissues.
Main Results:
- TRZ administration for 10 days induced cardiac dysfunction, myocardial injury, and fibrosis in mice.
- RNA-Seq identified 593 differentially expressed genes.
- The CD74/STAT1 signaling pathway was implicated, with increased CD74 and p-STAT1 expression, elevated apoptosis markers (Bax, Caspase-3), and inflammatory cytokines (IFN-γ, TNF-α).
Conclusions:
- Trastuzumab may induce cardiotoxicity by activating the CD74/STAT1 signaling pathway.
- This activation is associated with increased cardiomyocyte apoptosis and inflammation.
- Findings provide potential therapeutic targets for mitigating TRZ-related heart damage.
