Abstract：
Trastuzumab is a monoclonal antibody used in oncotherapy for HER2-positive tumors. However, as an adverse effect, trastuzumab elevates the risk of heart failure, implying the involvement of energy production and mitochondrial processes. Past studies with transcriptome analysis have offered insights on pathways related to trastuzumab safety and toxicity but limited study sizes hinder conclusive findings. Therefore, we meta-analyzed mitochondria-related gene expression data in trastuzumab-treated cardiomyocytes. We searched the transcriptome databases for trastuzumab-treated cardiomyocytes in the ArrayExpress, DDBJ Omics Archive, Gene Expression Omnibus, Google Scholar, PubMed, and Web of Science repositories. A subset of 1270 genes related to mitochondrial functions (biogenesis, organization, mitophagy, and autophagy) was selected from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology Resource databases to conduct the present meta-analysis using the Metagen package (Study register at PROSPERO: CRD42021270645). Three datasets met the inclusion criteria and 1243 genes were meta-analyzed. We observed 69 upregulated genes after trastuzumab treatment which were related mainly to autophagy (28 genes) and mitochondrial organization (28 genes). We also found 37 downregulated genes which were related mainly to mitochondrial biogenesis (11 genes) and mitochondrial organization (24 genes). The present meta-analysis indicates that trastuzumab therapy causes an unbalance in mitochondrial functions, which could, in part, help explain the development of heart failure and yields a list of potential molecular targets. These findings contribute to our understanding of the molecular mechanisms underlying the cardiotoxic effects of trastuzumab and may have implications for the development of targeted therapies to mitigate such effects.
摘要：
曲妥珠单抗是用于HER2阳性肿瘤的肿瘤治疗的单克隆抗体。然而,作为不利影响，曲妥珠单抗可提高心力衰竭的风险,暗示能量生产和线粒体过程的参与。过去的转录组分析研究提供了关于曲妥珠单抗安全性和毒性相关途径的见解，但有限的研究规模阻碍了结论性发现。因此,我们荟萃分析了曲妥珠单抗处理的心肌细胞线粒体相关基因表达数据.我们在ArrayExpress中搜索了用曲妥珠单抗处理的心肌细胞的转录组数据库，DDBJOmicsArchive,基因表达综合，谷歌学者，PubMed,和WebofScience存储库。与线粒体功能相关的1270个基因的子集(生物发生，组织,线粒体自噬,和自噬）从京都基因和基因组百科全书和基因本体论资源数据库中选择，使用Metagen软件包（PROSPERO的研究注册：CRD42021270645）进行本元分析。三个数据集符合纳入标准，对1243个基因进行了荟萃分析。我们在曲妥珠单抗治疗后观察到69个上调的基因，这些基因主要与自噬（28个基因）和线粒体组织（28个基因）有关。我们还发现了37个下调基因，这些基因主要与线粒体生物发生（11个基因）和线粒体组织（24个基因）有关。本荟萃分析表明曲妥珠单抗治疗导致线粒体功能失衡,这可能，在某种程度上,帮助解释心力衰竭的发展，并产生一系列潜在的分子靶标。这些发现有助于我们了解曲妥珠单抗心脏毒性作用的分子机制，并可能对开发靶向治疗以减轻此类作用具有意义。
