■乳腺癌是全世界最常见的恶性肿瘤。阿霉素是一种蒽环类药物,用于治疗乳腺癌,是首选治疗方法。然而,到目前为止,对阿霉素反应及其副作用的分子机制尚未全面了解。我们使用系统生物学和生物信息学方法来鉴定乳腺癌患者对阿霉素及其副作用的身体反应背后的必需基因和分子机制。
■提取并分析了组学数据,以构建蛋白质-蛋白质相互作用和基因调控网络。进行了网络分析以确定枢纽,瓶颈、集群,和调节基序,以评估身体对阿霉素及其副作用的反应背后的关键基因和分子机制。
■分析构建的PPI和基因-TF-miRNA调控网络显示,MCM3,MCM10和TP53是关键的枢纽瓶颈和种子蛋白。富集分析还揭示了细胞周期,TP53信令,叉头盒O(FoxO)信号,和病毒致癌作用是响应这种药物的基本途径。此外,囊泡运输和神经营养蛋白信号传导中的SNARE相互作用被鉴定为与阿霉素的副作用相关的途径。细胞凋亡的诱导,DNA修复,入侵抑制,转移,和DNA复制被认为是阿霉素抗癌作用的关键分子机制。SNARE在囊泡转运和神经营养蛋白信号传导中的相互作用以及葡萄糖代谢中的FoxO信号传导途径可能是导致阿霉素副作用的机制。
■在我们使用现有实验数据进行模型验证之后,我们推荐我们的其他新预测的生物标志物和通路作为乳腺癌中阿霉素应答的潜在分子机制和副作用,需要进一步研究.
UNASSIGNED: Breast cancer is the most common malignancy worldwide. Doxorubicin is an anthracycline used to treat breast cancer as the first treatment choice. Nevertheless, the molecular mechanisms underlying the response to Doxorubicin and its side effects are not comprehensively understood so far. We used systems biology and bioinformatics methods to identify essential genes and molecular mechanisms behind the body response to Doxorubicin and its side effects in breast cancer patients.
UNASSIGNED: Omics data were extracted and analyzed to construct the protein-protein interaction and gene regulatory networks. Network analysis was performed to identify hubs, bottlenecks, clusters, and regulatory motifs to evaluate crucial genes and molecular mechanisms behind the body response to Doxorubicin and its side effects.
UNASSIGNED: Analyzing the constructed PPI and gene-TF-miRNA regulatory network showed that MCM3, MCM10, and TP53 are key hub-bottlenecks and seed proteins. Enrichment analysis also revealed cell cycle, TP53 signaling, Forkhead box O (FoxO) signaling, and viral carcinogenesis as essential pathways in response to this drug. Besides, SNARE interactions in vesicular transport and neurotrophin signaling were identified as pathways related to the side effects of Doxorubicin. The apoptosis induction, DNA repair, invasion inhibition, metastasis, and DNA replication are suggested as critical molecular mechanisms underlying Doxorubicin anti-cancer effect. SNARE interactions in vesicular transport and neurotrophin signaling and FoxO signaling pathways in glucose metabolism are probably the mechanisms responsible for side effects of Doxorubicin.
UNASSIGNED: Following our model validation using the existing experimental data, we recommend our other newly predicted biomarkers and pathways as possible molecular mechanisms and side effects underlying the response to Doxorubicin in breast cancer requiring further investigations.