Dehghan Zeinab, Mirmotalebisohi Seyed Amir, Sameni Marzieh, Bazgiri Maryam, Zali Hakimeh
Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Avicenna J Med Biotechnol. 2022 Apr-Jun;14(2):137-153. doi: 10.18502/ajmb.v14i2.8889.
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.
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.
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.
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.
乳腺癌是全球最常见的恶性肿瘤。多柔比星是一种蒽环类药物，作为一线治疗药物用于治疗乳腺癌。然而，目前对多柔比星反应及其副作用背后的分子机制尚未完全了解。我们使用系统生物学和生物信息学方法来确定乳腺癌患者对多柔比星反应及其副作用背后的关键基因和分子机制。
提取并分析组学数据以构建蛋白质-蛋白质相互作用和基因调控网络。进行网络分析以识别枢纽、瓶颈、簇和调控基序，以评估机体对多柔比星反应及其副作用背后的关键基因和分子机制。
对构建的蛋白质-蛋白质相互作用（PPI）和基因-转录因子-微小RNA（TF-miRNA）调控网络的分析表明，微小染色体维持蛋白3（MCM3）、微小染色体维持蛋白10（MCM10）和肿瘤蛋白p53（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信号通路、叉头框O（FoxO）信号通路和病毒致癌作用是对该药物反应的重要途径。此外，囊泡运输中的可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）相互作用和神经营养因子信号通路被确定为与多柔比星副作用相关的途径。细胞凋亡诱导、DNA修复、侵袭抑制、转移和DNA复制被认为是多柔比星抗癌作用的关键分子机制。囊泡运输中的SNARE相互作用、葡萄糖代谢中的神经营养因子信号通路和FoxO信号通路可能是多柔比星副作用的机制。
在使用现有实验数据对我们的模型进行验证之后，我们推荐我们新预测的其他生物标志物和途径，作为乳腺癌中对多柔比星反应的潜在分子机制和副作用，需要进一步研究。
