|
|
基于WGCNA和网络药理学探讨小檗碱治疗结直肠癌的作用机制
|
Abstract:
目的：探讨小檗碱治疗结直肠癌的潜在治疗靶点和分子机制。方法：使用Swiss Target Prediction、Comparative Toxicogenomics、Target Net和Binding数据库筛选出小檗碱的活性成分及基因靶点。同时，基于GEO数据库的GSE90627数据集进行WGCNA分析，以识别结直肠癌的相关靶点。通过绘制维恩图以获得疾病–药物基因集。利用STRING数据库构建了蛋白互作网络(PPI)。利用Cytoscape软件进行拓扑分析，得到关键聚类。对关键簇基因进行了功能富集分析。最后，通过在线分子对接网站进行虚拟验证。结果：经过一系列的生物信息学分析，获得了包含35个基因的关键簇。富集分析结果表明，关键簇基因主要富集在p53和FOXO信号通路中。使用PPI和WGCNA分析鉴定出4个最重要的生物学靶标：WD重复蛋白74 (WDR 74)、细胞周期蛋白依赖性激酶4 (CDK 4)、极光激酶A (AURKA)和细胞周期蛋白1 (CCNE 1)。分子对接结果表明，上述4个靶标均能与小檗碱稳定结合。结论：本研究利用生物信息学和网络药理学方法筛选和鉴定了小檗碱治疗结直肠癌的生物学靶点和分子机制，为结直肠癌的诊断和治疗提供了新的建议和理论支持。
Objective: To explore the potential therapeutic target and molecular mechanism of berberine in the treatment of colorectal cancer. Methods: Swiss Target Prediction, Comparative Toxicogenomics, TargetNet and Binding databases were used to screen the active components and gene targets of berberine. In parallel, WGCNA analysis was performed based on the GSE90627 dataset from the GEO database to identify relevant targets for colorectal cancer. The disease-drug gene set is ob-tained by drawing a Venn diagram. A protein interaction network (PPI) was constructed using STRING database. Topology analysis was performed using Cytoscape software to obtain key cluster. The key cluster genes were analyzed for functional enrichment. Finally, virtual validation was per-formed through an online molecular docking website. Results: After a series of bioinformatics anal-yses, key clusters containing 35 genes were obtained. Enrichment analysis showed that key cluster genes were mainly enriched in p53 and FOXO signal pathways. Four of the most important biologi-cal targets were identified: WD repeat protein 74 (WDR74), cyclin dependent kinase 4 (CDK4), au-rora kinase A (AURKA), and cyclin E1 (CCNE 1). Molecular docking results showed that all four tar-gets could bind to berberine stably. Conclusion: In this study, biological targets and molecular mechanisms of berberine in the treatment of colorectal cancer were screened and identified by bi-oinformatics and network pharmacology methods, which provided new suggestions and theoretical support for the diagnosis and treatment of colorectal cancer.
| [1] | Kuipers, E.J., Grady, W.M., Lieberman, D., et al. (2015) Colorectal Cancer. Nature Reviews Disease Primers, 1, Article No. 15065. https://doi.org/10.1038/nrdp.2015.65 |
| [2] | Arnold, M., Sierra, M.S., Laversanne, M., et al. (2017) Global Patterns and Trends in Colorectal Cancer Incidence and Mortality. Gut, 66, 683-691. https://doi.org/10.1136/gutjnl-2015-310912 |
| [3] | Zhong, Y., Long, T., Gu, C.S., et al. (2021) MYH9-Dependent Polarization of ATG9B Promotes Colorectal Cancer Metastasis by Accelerating Focal Adhesion Assembly. Cell Death & Differentiation, 28, 3251-3269.
https://doi.org/10.1038/s41418-021-00813-z |
| [4] | Sung, H., Ferlay, J., Siegel, R.L., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249.
https://doi.org/10.3322/caac.21660 |
| [5] | Faugeras, L., Dili, A., Druez, A., et al. (2017) Treatment Options for Met-astatic Colorectal Cancer in Patients with Liver Dysfunction Due To Malignancy. Critical Reviews in Oncolo-gy/Hematolog, 115, 59-66.
https://doi.org/10.1016/j.critrevonc.2017.03.029 |
| [6] | Francescone, R., Hou, V. and Grivennikov, S.I. (2015) Cyto-kines, IBD, and Colitis-Associated Cancer. Inflammatory Bowel Diseases, 21, 409-418. https://doi.org/10.1097/MIB.0000000000000236 |
| [7] | Geng, F., Wang, Z., Yin, H., et al. (2017) Molecular Tar-geted Drugs and Treatment of Colorectal Cancer: Recent Progress and Future Perspectives. Cancer Biotherapy & Radio-pharmaceuticals, 32, 149-160.
https://doi.org/10.1089/cbr.2017.2210 |
| [8] | Wang, C.Z., Calway, T. and Yuan, C.S. (2012) Herbal Medicines as Adjuvants for Cancer Therapeutics. The American Journal of Chinese Medicine, 40, 657-669. https://doi.org/10.1142/S0192415X12500498 |
| [9] | Mao, D., Feng, L., Huang, S., et al. (2019) Meta-Analysis of Xihuang Pill Efficacy When Combined with Chemotherapy for Treatment of Breast Cancer. Evidence-Based Comple-mentary and Alternative Medicine, 2019, Article ID: 3502460. https://doi.org/10.1155/2019/3502460 |
| [10] | Zhang, Q., Chen, X., Luo, Y., et al. (2017) Fuzi Enhances Anti-Tumor Efficacy of Radiotherapy on Lung Cancer. Journal of Cancer, 8, 3945-3951. https://doi.org/10.7150/jca.22162 |
| [11] | Yu, C.T., Chen, T., Lu, S., et al. (2022) Identification of Significant Modules and Targets of Xian-Lian-Jie-Du Decoction Based on the Analysis of Transcriptomics, Prote-omics and Single-Cell Transcriptomics in Colorectal Tumor. Journal of Inflammation Research, 15, 1483-1499. https://doi.org/10.2147/JIR.S344861 |
| [12] | Huang, S., Zhang, Z., Li, W., et al. (2020) Network Pharmacolo-gy-Based Prediction and Verification of the Active Ingredients and Potential Targets of Zuojinwan for Treating Colorectal Cancer. Drug Design, Development and Therapy, 14, 2725-2740. https://doi.org/10.2147/DDDT.S250991 |
| [13] | Shi, H., Tian, S. and Tian, H. (2021) Network Pharmacology Inter-pretation of Fuzheng-Jiedu Decoction against Colorectal Cancer. Evidence-Based Complementary and Alternative Medi-cine, 2021, Article ID: 4652492.
https://doi.org/10.1155/2021/4652492 |
| [14] | Jiang, X., Jiang, Z., Jiang, M., et al. (2022) Berberine as a Potential Agent for the Treatment of Colorectal Cancer. Frontiers in Medicine, 9, Article 886996. https://doi.org/10.3389/fmed.2022.886996 |
| [15] | Xue, X., Zhao, X., Wang, J., et al. (2023) Carthami Flos Extract against Carbon Tetrachloride-Induced Liver Fibrosis via Alleviating Angiogenesis in Mice. Phytomedicine, 108, Article ID: 154517.
https://doi.org/10.1016/j.phymed.2022.154517 |
| [16] | Li, S.Y., Shi, C.J., Fu, W.M., et al. (2023) Berberine Inhibits Tumour Growth in Vivo and in Vitro through Suppressing the LincROR-Wnt/β-Catenin Regulatory Axis in Colorectal Cancer. Journal of Pharmacy and Pharmacology, 75, 129-138. https://doi.org/10.1093/jpp/rgac067 |
| [17] | Berger, S.I. and Iyengar, R. (2009) Network Analyses in Systems Pharmacology. Bioinformatics, 25, 2466-2472.
https://doi.org/10.1093/bioinformatics/btp465 |
| [18] | Zeng, L. and Yang, K. (2017) Exploring the Pharmacological Mechanism of Yanghe Decoction on HER2-Positive Breast Cancer by a Network Pharmacology Approach. Journal of Ethnopharmacology, 199, 68-85.
https://doi.org/10.1016/j.jep.2017.01.045 |
| [19] | Ritchie, M.E., Phipson, B., Wu, D., et al. (2015) Limma Powers Differential Expression Analyses for RNA-Sequencing and Microarray Studies. Nucleic Acids Research, 43, e47. https://doi.org/10.1093/nar/gkv007 |
| [20] | Gu, Z., Eils, R. and Schlesner, M. (2016) Complex Heatmaps Reveal Pat-terns and Correlations in Multidimensional Genomic Data. Bioinformatics, 32, 2847-2849. https://doi.org/10.1093/bioinformatics/btw313 |
| [21] | Miao, X., Luo, Q., Zhao, H., et al. (2016) Co-Expression Analysis and Identification of Fecundity-Related Long Non-Coding RNAs in Sheep Ovaries. Scientific Reports, 6, Arti-cle No. 39398. https://doi.org/10.1038/srep39398 |
| [22] | Jiang, S., Zhang, Q., Su, Y. and Pan, L.Q. (2018) Net-work-Based Differential Analysis to Identify Molecular Features of Tumorigenesis for Esophageal Squamous Carcinoma. Molecules, 23, Article 88.
https://doi.org/10.3390/molecules23010088 |
| [23] | Berman, H.M., Westbrook, J., Feng, Z., et al. (2000) The Protein Data Bank. Nucleic Acids Research, 28, 235-242.
https://doi.org/10.1093/nar/28.1.235 |
| [24] | Surget, S., Khoury, M.P. and Bourdon, J.C. (2013) Uncovering the Role of P53 Splice Variants in Human Malignancy: A Clinical Perspective. OncoTargets and Therapy, 7, 57-68. https://doi.org/10.2147/OTT.S53876 |
| [25] | Ventura, A., Kirsch, D.G., Mclaughlin, M.E., et al. (2007) Restoration of P53 Function Leads to Tumour Regression in Vivo. Nature, 445, 661-665. https://doi.org/10.1038/nature05541 |
| [26] | Wang, J., Li, Y., Ding, M., et al. (2017) Molecular Mechanisms and Clinical Applications of MiR-22 in Regulating Malignant Progression in Human Cancer (Review). International Journal of Oncology, 50, 345-355.
https://doi.org/10.3892/ijo.2016.3811 |
| [27] | Ho, K.K., Myatt, S.S. and Lam, E.W. (2008) Many Forks in the Path: Cycling with FoxO. Oncogene, 27, 2300-2311.
https://doi.org/10.1038/onc.2008.23 |
| [28] | Myatt, S.S. and Lam, E.W. (2007) The Emerging Roles of Forkhead Box (Fox) Proteins in Cancer. Nature Reviews Cancer, 7, 847-859. https://doi.org/10.1038/nrc2223 |
| [29] | Bernard, R., Getachew, R., Kamato, D., et al. (2016) Evaluation of the Potential Synergism of Imatinib-Related Poly Kinase Inhibitors Using Growth Factor Stimulated Proteoglycan Synthesis as a Model Response. Journal of Pharmacy and Pharmacology, 68, 368-378. https://doi.org/10.1111/jphp.12530 |
| [30] | Lo, Y.H., Romes, E.M., Pillon, M.C., et al. (2017) Structural Analysis Reveals Features of Ribosome Assembly Factor Nsa1/WDR74 Important for Localization and Interaction with Rix7/NVL2. Structure, 25, 762-772.E4.
https://doi.org/10.1016/j.str.2017.03.008 |
| [31] | Li, Y., Zhou, Y., Li, B., et al. (2020) WDR74 Modulates Melanoma Tumorigenesis and Metastasis through the RPL5- MDM2-P53 Pathway. Oncogene, 39, 2741-2755. https://doi.org/10.1038/s41388-020-1179-6 |
| [32] | Cai, Z., Mei, Y., Jiang, X. and Shi, X.F. (2021) WDR74 Pro-motes Proliferation and Metastasis in Colorectal Cancer Cells through Regulating the Wnt/β-Catenin Signaling Pathway. Open Life Sciences, 16, 920-929.
https://doi.org/10.1515/biol-2021-0096 |
| [33] | Wang, C., Li, H., Wu, L., et al. (2021) Coiled-Coil Do-main-Containing 68 Downregulation Promotes Colorectal Cancer Cell Growth by Inhibiting ITCH-Mediated CDK4 Degradation. Frontiers in Oncology, 11, Article 668743.
https://doi.org/10.3389/fonc.2021.668743 |
| [34] | Assi, T., Kattan, J., Rassy, E., et al. (2020) Targeting CDK4 (Cy-clin-Dependent Kinase) Amplification in Liposarcoma: A Comprehensive Review. Critical Reviews in Oncolo-gy/Hematology, 153, Article ID: 103029.
https://doi.org/10.1016/j.critrevonc.2020.103029 |
| [35] | Carvajal, R.D., Tse, A. and Schwartz, G.K. (2006) Aurora Kinases: New Targets for Cancer Therapy. Clinical Cancer Research, 12, 6869-6875. https://doi.org/10.1158/1078-0432.CCR-06-1405 |
| [36] | Liu, F., Zhang, Y., Dong, Y., et al. (2021) Knockdown of AURKA Sensitizes the Efficacy of Radiation in Human Colorectal Cancer. Life Sciences, 271, Article ID: 119148. https://doi.org/10.1016/j.lfs.2021.119148 |
| [37] | Casorzo, L., Dell’aglio, C., Sarotto, I., et al. (2015) Aurora kinase A Gene Copy Number Is Associated with the Malignant Transformation of Colorectal Adenomas but Not with the Serrated Neoplasia Progression. Human Pathology, 46, 411-418. https://doi.org/10.1016/j.humpath.2014.11.016 |
| [38] | Shan, B., Zhao, R., Zhou, J., et al. (2020) AURKA Increase the Chemosensitivity of Colon Cancer Cells to Oxaliplatin by In-hibiting the TP53-Mediated DNA Damage Response Genes. BioMed Research International, 2020, Article ID: 8916729. https://doi.org/10.1155/2020/8916729 |
| [39] | Li, X., Wu, Y., Hui, D., et al. (2021) Multiple Bronchiolar Adenomas with Malignant Transformation and CCNE1 Mutation: A Case Report and Literature Review. Journal of Cardiothoracic Surgery, 16, Article No. 307.
https://doi.org/10.1186/s13019-021-01687-5 |
