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生物信息学对胰腺癌细胞外基质有关基因的研究
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Abstract:
通过生物信息学方法挖掘胰腺癌组织中差异基因,明确差异基因的功能与信号通路,筛选出与细胞外基质有关的信号通路,确定细胞外基质通路研究与胰腺癌之间的关系,找寻胰腺癌中外基质的潜在生物标志物。从Gene Expression Omnibus (GEO)数据库中下载胰腺癌样本数据,基于GSE91035芯片数据,运用R语言筛选数据中的差异表达基因(differentially expressed genes, DGEs),对胰腺癌DGEs进行基因本体功能注释(GO)和京都基因与基因组百科全书通路分析(KEGG)。利用GSEA数据库构建细胞外基质通路可视化,并确定关键基因,用GEPIA2数据库验证关键基因的表达与预后的关系。结果确定有3023个差异基因,上调1803个,下调1220个。其中和细胞外基质相关的基因为COL1A1,LAMB3,COMP,FN1,THBS2,LAMC2,ITGA11,ITGB6,COL4A5,HMMR并对其进行验证确定LAMB3,ITGB6,HMMR三个基因与胰腺癌的发生发展相关。该数据集的差异基因主要通过参与抗原加工和呈递,ECM受体相互作用,细胞粘附分子,细胞黏附等生物学过程从而影响胰腺癌的发生发展,并确定细胞外基质有关基因对胰腺癌至关重要。本研究通过对胰腺癌差异基因的分析,确定细胞外基质有关基因可以作为关键影响靶点。
This paper aims to identify differentially expressed genes (DGEs) in pancreatic cancer tissues using bioinformatics methods, elucidate the functions and signaling pathways of these DGEs, screen out signaling pathways related to the extracellular matrix (ECM), determine the relationship between ECM pathway research and pancreatic cancer, and identify potential biomarkers of the ECM in pancreatic cancer. Sample data of pancreatic cancer were downloaded from the Gene Expression Omnibus (GEO) database. Based on the chip data from GSE91035, R language was used to screen DGEs in the data. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the DGEs related to pancreatic cancer. The GSEA database was utilized to visualize the ECM pathway and identify key genes. The GEPIA2 database was employed to verify the relationship between the expression of these key genes and prognosis. A total of 3023 DGEs were identified, with 1803 upregulated and 1220 downregulated genes. Among them, genes related to the ECM included COL1A1, LAMB3, COMP, FN1, THBS2, LAMC2, ITGA11, ITGB6, COL4A5, and HMMR. Verification was conducted to confirm that LAMB3, ITGB6, and HMMR are associated with the occurrence and development of pancreatic cancer. The DGEs in this dataset primarily affect the occurrence and development of pancreatic cancer by participating in biological processes such as antigen processing and presentation, ECM receptor interaction, cell adhesion molecules, and cell adhesion. It was determined that genes related to the ECM are crucial in pancreatic cancer. Through the analysis of DGEs in pancreatic cancer, this study identified genes related to the ECM as key targets of influence.
[1] | Mukhopadhyay, S., Vander Heiden, M.G. and McCormick, F. (2021) The Metabolic Landscape of Ras-Driven Cancers from Biology to Therapy. Nature Cancer, 2, 271-283. https://doi.org/10.1038/s43018-021-00184-x |
[2] | 张彩霞, 林能明. 吉西他滨药代动力学研究进展[J]. 肿瘤学杂志, 2004, 10(4): 271-274. |
[3] | 谢燕鸣, 王连心, 王永炎. 临床联合用药机制研究探讨[J]. 中国中药杂志, 2014, 39(18): 3424-3426. |
[4] | Maksimenko, A., Caron, J., Mougin, J., Desmaële, D. and Couvreur, P. (2015) Gemcitabine-Based Therapy for Pancreatic Cancer Using the Squalenoyl Nucleoside Monophosphate Nanoassemblies. International Journal of Pharmaceutics, 482, 38-46. https://doi.org/10.1016/j.ijpharm.2014.11.009 |
[5] | Pirker, R. (2020) Chemotherapy Remains a Cornerstone in the Treatment of Nonsmall Cell Lung Cancer. Current Opinion in Oncology, 32, 63-67. https://doi.org/10.1097/cco.0000000000000592 |
[6] | 刘成裕, 刘广宣. 胰腺癌细胞吉西他滨耐药机制研究进展[J]. 人民军医, 2019, 62(12): 1211-1213, 1216. |
[7] | Lavie, D., Ben-Shmuel, A., Erez, N. and Scherz-Shouval, R. (2022) Cancer-Associated Fibroblasts in the Single-Cell Era. Nature Cancer, 3, 793-807. https://doi.org/10.1038/s43018-022-00411-z |
[8] | Boumahdi, S. and de Sauvage, F.J. (2019) The Great Escape: Tumour Cell Plasticity in Resistance to Targeted Therapy. Nature Reviews Drug Discovery, 19, 39-56. https://doi.org/10.1038/s41573-019-0044-1 |
[9] | Linares, J., Sallent-Aragay, A., Badia-Ramentol, J., Recort-Bascuas, A., Méndez, A., Manero-Rupérez, N., et al. (2023) Long-term Platinum-Based Drug Accumulation in Cancer-Associated Fibroblasts Promotes Colorectal Cancer Progression and Resistance to Therapy. Nature Communications, 14, Article No. 746. https://doi.org/10.1038/s41467-023-36334-1 |
[10] | 王莹, 周芳. 肿瘤代谢重排与肿瘤耐药相关性的研究进展[J]. 药物评价研究, 2019, 42(3): 378-384. |
[11] | Jhunjhunwala, S., Hammer, C. and Delamarre, L. (2021) Antigen Presentation in Cancer: Insights into Tumour Immunogenicity and Immune Evasion. Nature Reviews Cancer, 21, 298-312. https://doi.org/10.1038/s41568-021-00339-z |
[12] | Li, W. and Kang, Y. (2016) Probing the Fifty Shades of EMT in Metastasis. Trends in Cancer, 2, 65-67. https://doi.org/10.1016/j.trecan.2016.01.001 |
[13] | 何玉鑫. 长链非编码RNA UCA1通过MAPK通路调节线粒体动力学促进胰腺癌进展[D]: [硕士学位论文]. 镇江: 江苏大学, 2022. |
[14] | Gautam, S.K., Batra, S.K. and Jain, M. (2023) Molecular and Metabolic Regulation of Immunosuppression in Metastatic Pancreatic Ductal Adenocarcinoma. Molecular Cancer, 22, Article No. 118. https://doi.org/10.1186/s12943-023-01813-y |
[15] | Feng, B., Wu, J., Shen, B., Jiang, F. and Feng, J. (2022) Cancer-Associated Fibroblasts and Resistance to Anticancer Therapies: Status, Mechanisms, and Countermeasures. Cancer Cell International, 22, Article No. 166. https://doi.org/10.1186/s12935-022-02599-7 |
[16] | Weadick, B., Nayak, D., Persaud, A.K., Hung, S.W., Raj, R., Campbell, M.J., et al. (2021) EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1. Molecular Cancer Therapeutics, 20, 410-422. https://doi.org/10.1158/1535-7163.mct-20-0316 |
[17] | Yang, C., Sheng, Y., Shi, X., Liu, Y., He, Y., Du, Y., et al. (2020) CD44/HA Signaling Mediates Acquired Resistance to a PI3Kα Inhibitor. Cell Death & Disease, 11, Article No. 831. https://doi.org/10.1038/s41419-020-03037-0 |
[18] | Gomez, K.E., Wu, F., Keysar, S.B., Morton, J.J., Miller, B., Chimed, T., et al. (2020) Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells. Cancer Research, 80, 4185-4198. https://doi.org/10.1158/0008-5472.can-20-1079 |
[19] | Assmann, V., Jenkinson, D., Marshall, J.F. and Hart, I.R. (1999) The Intracellular Hyaluronan Receptor RHAMM/IHABP Interacts with Microtubules and Actin Filaments. Journal of Cell Science, 112, 3943-3954. https://doi.org/10.1242/jcs.112.22.3943 |
[20] | Liang, B., Li, L., Miao, R., Wang, J., Chen, Y., Li, Z., et al. (2019) Expression of Interleukin-6 and Integrin ΑΝβ6 in Colon Cancer: Association with Clinical Outcomes and Prognostic Implications. Cancer Investigation, 37, 174-184. https://doi.org/10.1080/07357907.2019.1597103 |
[21] | 潘少伟, 张华莉. CRISPR⁃Cas9系统的发现[J]. 中南大学学报(医学版), 2021, 4(12): 1392-1402. |
[22] | 肖斌, 全静雯, 陈丽丹, 等. 基于CRISPR/Cas9技术构建真核细胞激酶敲除文库质粒[J]. 实用医学杂志, 2017, 33(24): 4038-4042. |
[23] | 段键, 何金兰, 曾仲. 结直肠癌肝转移的多学科团队治疗[J]. 中华消化外科杂志, 2021, 20(12): 1370-1372. |
[24] | Jung, S., Lim, H.S., Liu, L., Chang, J.W., Lim, Y.C., Rha, K.S., et al. (2018) LAMB3 Mediates Metastatic Tumor Behavior in Papillary Thyroid Cancer by Regulating C-MET/Akt Signals. Scientific Reports, 8, Article No. 2718. https://doi.org/10.1038/s41598-018-21216-0 |
[25] | Volpi, A, D’Elia, G., Pannarale, O.C., et al. (2011) Overexpression of Laminine5(LN-5) in Peritoneal Lavage of Colorectal Cancer Patients Preliminary Results. Il Giornale di Chirurgia, 32, 59-63. |
[26] | Kita, Y., Mimori, K., Tanaka, F., Matsumoto, T., Haraguchi, N., Ishikawa, K., et al. (2009) Clinical Significance of LAMB3 and COL7A1 mRNA in Esophageal Squamous Cell Carcinoma. European Journal of Surgical Oncology (EJSO), 35, 52-58. https://doi.org/10.1016/j.ejso.2008.01.025 |
[27] | Liu, L., Jung, S., Oh, C., Lee, K., Won, H., Chang, J.W., et al. (2019) LAMB3 Is Associated with Disease Progression and Cisplatin Cytotoxic Sensitivity in Head and Neck Squamous Cell Carcinoma. European Journal of Surgical Oncology, 45, 359-365. https://doi.org/10.1016/j.ejso.2018.10.543 |