Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
Cardiovasc Toxicol. 2023 Oct;23(9-10):329-348. doi: 10.1007/s12012-023-09806-5. Epub 2023 Sep 8.
Based on a few studies, heart failure patients with breast cancer were assessed to find potential biomarkers for doxorubicin-induced cardiotoxicity. However, key immune-related transcriptional markers linked to doxorubicin-induced cardiotoxicity in breast cancer patients have not been thoroughly investigated. We used GSE40447, GSE76314, and TCGA BRCA cohorts to perform this study. Then, we performed various bioinformatics approaches to identify the key immune-related transcriptional markers and their association with doxorubicin-induced cardiotoxicity in patients with breast cancer. We found 255 upregulated genes and 286 downregulated genes in patients with doxorubicin-induced heart failure in breast cancer. We discovered that in patients with breast cancer comorbidity doxorubicin-induced cardiotoxicity, the 58 immunological genes are elevated (such as CPA3, VSIG4, GATA2, RFX2, IL3RA, and LRP1), and the 60 genes are significantly suppressed (such as MS4A1, FCRL1, CD200, FCRLA, FCRL2, and CD79A). Furthermore, we revealed that the immune-related differentially expressed genes (DEGs) are substantially associated with the enrichment of KEGG pathways, including B-cell receptor signaling pathway, primary immunodeficiency, chemokine signaling pathway, hematopoietic cell lineage, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, MAPK signaling pathway, focal adhesion, dilated cardiomyopathy, cell adhesion molecule, etc. Moreover, we discovered that the doxorubicin-induced immune-related genes are crucially involved in the protein-protein interaction and gene clusters. The immune-related genes, including IFIT5, XCL1, SPIB, BTLA, MS4A1, CD19, TCL1A, CD83, CD200, FCRLA, CD79A, BIRC3, and IGF2R are significantly associated with a poor survival prognosis of breast cancer patients and showed diagnostic efficacy in patients with breast cancer and heart failure. Molecular docking revealed that the survival-associated genes interact with the doxorubicin with appreciable binding affinity. Finally, we validated the expression level of immune-related genes in breast cancer patients-derived cardiomyocytes with doxorubicin-induced cardiotoxicity and found that the level of RAD9A, HSPA1B, GATA2, IGF2R, CD200, ERCC8, and BCL11A genes are consistently dysregulated. Our findings offered a basis for understanding the mechanism and pathogenesis of the cardiotoxicity caused by doxorubicin in breast cancer patients and predicted the interaction of immune-related potential biomarkers with doxorubicin.
基于一些研究，评估了患有乳腺癌的心力衰竭患者，以寻找多柔比星诱导的心脏毒性的潜在生物标志物。然而，与乳腺癌患者多柔比星诱导的心脏毒性相关的关键免疫相关转录标志物尚未得到深入研究。我们使用 GSE40447、GSE76314 和 TCGA BRCA 队列进行了这项研究。然后，我们采用了各种生物信息学方法来鉴定关键的免疫相关转录标志物及其与乳腺癌患者多柔比星诱导的心脏毒性的关联。我们发现患有乳腺癌的多柔比星诱导性心力衰竭患者中有 255 个上调基因和 286 个下调基因。我们发现，在患有乳腺癌合并症的多柔比星诱导性心脏毒性患者中，58 个免疫基因升高（如 CPA3、VSIG4、GATA2、RFX2、IL3RA 和 LRP1），而 60 个基因显著受抑制（如 MS4A1、FCRL1、CD200、FCRLA、FCRL2 和 CD79A）。此外，我们揭示了免疫相关差异表达基因（DEGs）与 KEGG 途径的富集显著相关，包括 B 细胞受体信号通路、原发性免疫缺陷、趋化因子信号通路、造血细胞谱系、细胞因子-细胞因子受体相互作用、Toll 样受体信号通路、MAPK 信号通路、黏附斑、扩张型心肌病、细胞黏附分子等。此外，我们发现多柔比星诱导的免疫相关基因与蛋白质-蛋白质相互作用和基因簇密切相关。免疫相关基因，包括 IFIT5、XCL1、SPIB、BTLA、MS4A1、CD19、TCL1A、CD83、CD200、FCRLA、CD79A、BIRC3 和 IGF2R，与乳腺癌患者的不良生存预后显著相关，并在乳腺癌和心力衰竭患者中显示出诊断疗效。分子对接显示，与生存相关的基因与多柔比星具有可观的结合亲和力。最后，我们在多柔比星诱导的心脏毒性的乳腺癌患者衍生的心肌细胞中验证了免疫相关基因的表达水平，发现 RAD9A、HSPA1B、GATA2、IGF2R、CD200、ERCC8 和 BCL11A 基因的水平均失调。我们的研究结果为理解多柔比星引起的乳腺癌患者心脏毒性的机制和发病机制提供了依据，并预测了免疫相关潜在生物标志物与多柔比星的相互作用。
