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| 丙泊酚减少乳腺癌患者术后复发率的网络药理学和分子对接分析 |
| Network pharmacology and molecular docking analysis of propofol in reducing postoperative recurrence rate of breast cancer patients |
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| DOI：10.12089/jca.2023.01.012 |
| 中文关键词: 丙泊酚 乳腺癌 网络药理学 雌激素受体α |
| 英文关键词: Propofol Breast cancer Network pharmacology Estrogen receptors alpha |
| 基金项目: |
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| 中文摘要: |
目的 乳腺癌患者术后血液里的肿瘤细胞数是复发率升高和生存率降低的独立影响因素。丙泊酚虽然已经被证实能减少乳腺癌患者术后血液循环里的肿瘤数，但是丙泊酚是否能直接与乳腺癌细胞相互作用、通过什么受体与乳腺癌细胞相互作用仍然处于未知状态，因此本研究通过网络药理学技术、癌症基因组图谱（TCGA）数据挖掘、分子对接技术试图探索出丙泊酚与乳腺癌细胞直接作用的靶点及相关的通路。
方法 在PubChem数据库中检索出丙泊酚的3D结构和Canonical smiles序列并在Swiss Target prediction、Chembl、Drugbank三个数据库中整合出丙泊酚的作用位点，在Uniprot数据库中转换成基因名称。在DisGeNet、Gene cards数据库中检索出与乳腺癌相关的基因。将上述两组基因数据集取交集得到19个共有基因。将得到的基因进行京都基因与基因组百科全书（KEGG）、基因本体论（GO）富集分析。筛选出与乳腺癌相关的KEGG通路和基因，并在TCGA乳腺癌的基因表达数据集中对筛选出的基因进行验证。最后使用分子对接技术将丙泊酚分子和雌激素受体α（ESRα）进行对接验证。
结果 丙泊酚作用靶点数据集与乳腺癌相关基因数据集有19个共有基因，KEGG分析中雌激素信号通路是与乳腺癌最相关的通路，富集在这条通路上的基因有γ氨基丁酸B型受体基因（GABBR1，GABBR2）、雌激素受体基因（ESR1）。在TCGA乳腺癌基因表达数据集中分析上述3个基因在肿瘤组织和非肿瘤组织中的差异性表达情况，发现上述3个基因在肿瘤组织和非肿瘤组织中存在明显的差异性表达，分子对接结果显示丙泊酚与ESRα结合良好。
结论 丙泊酚可能通过与乳腺癌细胞膜上的GABAB受体和雌激素受体结合，影响乳腺癌细胞的“膜启动类固醇信号传导”，从而减少乳腺癌细胞术中的微转移，减少乳腺癌患者术后血液循环内的肿瘤细胞数量，最终减少乳腺癌患者术后复发率。 |
| 英文摘要: |
Objective The number of circulating tumor cells is independently associated with a higher risk of disease recurrence and with reduced survival in breast cancer patients after surgery. Although propofol has been shown to reduce the number of tumors in the blood circulation of patients with breast cancer after surgery, it is still unknown whether or not propofol can directly interact with breast cancer cells and what receptors it binds to. Therefore, we used network pharmacology technology, The Cancer Genome Atlas (TCGA) data mining and molecular docking technology to try to explore the direct targets and related pathways of propofol and breast cancer cells.
Methods The 3D structure and Canonical Smiles sequence of propofol were retrieved from Pubchem database, and the protein targets of propofol were predicted in Swiss Target Prediction, Chembl and Drugbank databases, and then the gene names of the targets were extracted from the Uniprot database to obtain the gene target dataset of propofol. The dataset of disease targets for breast cancer was obtained from the DisGeNet and Gene Cards datasets, and 19 genes were obtained by taking the intersection of the above-mentioned two gene datasets. GO and KEGG enrichment analyses of the 19 genes were then conducted to screen out the KEGG and genes associated with breast cancer and validated in TCGA database. Finally, molecular docking was used to verify the interaction of propofol and Estrogen receptors α (ESRα).
Results Nineteen genes were common for both sets of genes and Gene-set enrichment analysis revealed that GABBR1, GABBR2, ESR1 were enriched on the Estrogen signaling pathway, which were significantly associated with the breast cancer. According to the TCGA breast invasive carcinoma gene expression dataset, differential expressions between the tumor tissue and the nontumor tissue were shown on the above three genes which ESR1 was most differentially expressed. Besides, molecular docking showed the effective binding between propofol and ESRα receptors.
Conclusion Perioperative use of propofol may affect the “membrane-initiated steroid signaling” of breast cancer cells through binding with GABAB receptors and estrogen receptors on the breast cancer cell membrane, thus reducing the micrometastasis of breast cancer cells during surgery, reducing the number of tumor cells in the blood circulation of breast cancer patients after surgery, and ultimately reducing the postoperative recurrence rate of breast cancer patients. |
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