Bioinformatic Analysis of Peripheral Blood miRNA of Breast Cancer Patients in Relation With Anthracycline Cardiotoxicity

Abstract

The current diagnostic methods and treatments still fail to lower the incidence of anthracyclineinduced cardiotoxicity effectively. In this study, we aimed to (1) analyze the cardiotoxicity-related genes after breast cancer chemotherapy in gene expression database and (2) carry out bioinformatic analysis to identify cardiotoxicity-related abnormal expressions, the biomarkers of such abnormal expressions, and the key regulatory pathways after breast cancer chemotherapy. Cardiotoxicityrelated gene expression data (GSE40447) after breast cancer chemotherapy was acquired from the GEO database. The biomarker expression data of women with chemotherapy-induced cardiotoxicity (group A), chemotherapy history but no cardiotoxicity (group B), and confirmatory diagnosis of breast cancer but normal ejection fraction before chemotherapy (group C) were analyzed to obtain the mRNA with differential expressions and predict the miRNAs regulating the differential expressions.The miRanda formula and functional enrichment analysis were used to screen abnormal miRNAs.Then, the gene ontology (GO) analysis was adapted to further screen the miRNAs related to cardiotoxicity after breast cancer chemotherapy. The data of differential analysis of biomarker expression of groups A, B, and C using the GSE40447-related gene expression profile database showed that there were 30 intersection genes. The differentially expressed mRNAs were predicted using the miRanda and TargetScan software, and a total of 2978 miRNAs were obtained by taking the intersections. Further, the GO analysis and targeted regulatory relationship between miRNA and target genes were used to establish miRNA-gene interaction network to screen and obtain 7 cardiotoxicity-related miRNAs with relatively high centrality, including hsa-miR-4638-3p, hsa-miR-5096, hsa-miR-4763-5p, hsa-miR-1273g-3p, hsa-miR6192, hsa-miR-4726-5p and hsa-miR-1273a.Among them, hsa-miR-4638-3p and hsa-miR-1273g-3p had the highest centrality. The PCR verification results were consistent with those of the chip data. There are differentially expressed miRNAs in the peripheral blood of breast cancer patients with anthracycline cardiotoxicity. Among them, hsa-miR-4638-3p and hsa-miR-1273g-3p are closely associated with the onset of anthracycline cardiotoxicity in patients with breast cancer. Mining, integrating, and validating effective information resources of biological gene chips can provide a new direction for further studies on the molecular mechanism of 3 anthracycline cardiotoxicity.

Potential roles of hsa_circ_000839 and hsa_circ_0005986 in breast cancer

“…The SMAD3, ZEB1, SNAI2, FOXM1, NFKB1, SMAD7, E2F1, ATF3, and hsa‐mir‐1200 had the most interaction among the mRNAs, and miRNA, respectively. There are copious experimental studies that suggest almost all of these genes have a pivotal role in BC development, invasion, and metastasis and the interaction of hsa_circ_000839 with them can augment our hypothesis about its association with BC circumstances 47‐55 . Also, bioinformatics construction of the hsa_circ_0005986/miRNA/mRNA network suggests that the GLI1, SMAD4, SP1, and FOXO4, and hsa‐mir‐326, and hsa‐mir‐421 had the most interaction among the mRNAs and miRNA, respectively.…”

A systematic review of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients reveals potentially clinically informative panels as well as key challenges in miRNA research

“…Clinical studies of breast cancer patients indicate that dysregulation of several miRNAs have been noted following anthracycline treatment [28][29][30][31][32][33][34][35], as summarised in Table 1. Many of the miRNAs examined were related to functions associated with cardiac damage such as apoptosis, hypertrophy and inflammatory responses which suggests that they could be used as potential biomarkers for the incidence of anthracycline induced cardiotoxicity.…”

“…Based on a systematic review of existing literature, 29 miRNA markers were identified for the investigation of chemotherapy induced cardiotoxicity (CIC) in breast cancer patients [28][29][30][31][32][33][34][35] (Table 1). However, a lack of replication of results amongst miRNA studies is highlighted as a major limitation of identifying informative miRNA markers, with many studies producing conflicting results or not supporting previously observed significant changes in miRNA expression.…”

Solamargine inhibits the growth of hepatocellular carcinoma and enhances the anticancer effect of sorafenib by regulating HOTTIP‐TUG1/miR‐4726‐5p/MUC1 pathway

“…21 MiR-4726-5p is also correlated with anthracycline cardiotoxicity in breast cancer patients. 22 Apart from that, miR-4726-5p may mediate the function of hematopoietic stem cells and the process of intervertebral disc degeneration. 23,24 However, miR-4726-5p has been still rarely studied in human cancer.…”