层粘连蛋白基因家族在低级别胶质瘤中的表达及功能的生物信息学分析
Bioinformatics Analysis of Expression and Function of Laminin Family Genes in Low-Grade Glioma
DOI: 10.12677/ACM.2023.134901, PDF,    科研立项经费支持
作者: 王金朝*:山东第一医科大学附属省立医院神经外科,山东 济南;山东第一医科大学研究生院,山东 济南;许尚臣#:山东第一医科大学附属省立医院神经外科,山东 济南
关键词: 低级别胶质瘤层粘连蛋白基因家族生物信息学细胞外基质Low-Grade Glioma Laminin Family Genes Bioinformatics Extracellular Matrix
摘要: 为了分析层粘连蛋白基因家族在低级别胶质瘤中的表达和预后评估价值,我们使用生物信息学数据挖掘方法。具体而言,我们从不同数据库下载了低级别胶质瘤的表达数据和临床信息,然后使用R验证了不同级别胶质瘤的表达情况,并测算了低级别胶质瘤的生存情况。接着,我们使用ROC预测模型验证了我们的结果。此外,我们还利用了cBioPortal、String、GeneMANIA和DAVID数据库,分析了层粘连蛋白基因家族在低级别胶质瘤中的基因变异、蛋白–蛋白相互作用,并进行了功能富集分析。研究结果表明,LAMA4、LAMA5、LAMB1、LAMB2、LAMB4、LAMC1、LAMC2和LAMC3是低级别胶质瘤中的明显促癌基因,与临床WHO分期密切相关,并且在2、3、4级中的表达逐级升高。另外,LAMA3是抑癌基因,表达量随着WHO级别的升高而降低。预后分析表明,除了LAMC2基因以外,所有基因和低级别胶质瘤的生存都具有统计学意义。TCGA数据库和cBioPortal工具的分析显示,这些基因的变异率相对较低。功能富集分析表明,层粘连蛋白基因家族的主要癌症相关功能涉及细胞外基质、细胞黏附和癌症相关信号等。因此,我们得出结论:层粘连蛋白家族分子可以作为低级别患者肿瘤分级和预后判断的潜在靶标,这一发现可能为胶质瘤的研究和个体化治疗提供一个新的视角。
Abstract: To investigate the expression and prognostic value of laminin family genes in low-grade glioma, we conducted a bioinformatics data mining analysis. We obtained expression data and clinical infor-mation for low-grade glioma from various databases, validated the expression of different grades of glioma using R, calculated survival outcomes for low-grade glioma, and applied an ROC prediction model for validation. Furthermore, we analyzed gene variations and protein-protein interactions of laminin family genes in low-grade glioma using cBioPortal, String, GeneMANIA, and DAVID data-bases, and performed functional enrichment analysis. Our results showed that LAMA4, LAMA5, LAMB1, LAMB2, LAMB4, LAMC1, LAMC2, and LAMC3 were significantly oncogenic in low-grade glio-ma, closely associated with clinical WHO staging, and exhibited progressively increasing expression levels in grades 2 to 4. Conversely, LAMA3 was found to be a tumor suppressor, with expression lev-els decreasing with increasing WHO grade. Survival analysis indicated that all genes except LAMC2 were statistically significant in low-grade glioma. The TCGA database and cBioPortal analysis re-vealed relatively low mutation rates for these genes. Functional enrichment analysis revealed that the main cancer-related functions of laminin family genes involved extracellular matrix, cell adhe-sion, and cancer-related signaling. In conclusion, laminin family molecules may serve as potential targets for low-grade glioma grading and prognosis, providing a new perspective for research and personalized treatment of glioma.
文章引用:王金朝, 许尚臣. 层粘连蛋白基因家族在低级别胶质瘤中的表达及功能的生物信息学分析[J]. 临床医学进展, 2023, 13(4): 6406-6416. https://doi.org/10.12677/ACM.2023.134901

参考文献

[1] Griveau, A., Seano, G., Shelton, S.J., Kupp, R., Jahangiri, A., Obernier, K., Krishnan, S., Lindberg, O.R., Yuen, T.J., Tien, A.-C., et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Mi-croenvironment. Cancer Cell, 33, 874-889. [Google Scholar] [CrossRef] [PubMed]
[2] Schiff, D. (2017) Low-Grade Gliomas. Continuum, 23, 1564-1579. [Google Scholar] [CrossRef
[3] Schiff, D., Van den Bent, M., Vogelbaum, M.A., Wick, W., Miller, C.R., Taphoorn, M., Pope, W., Brown, P.D., Platten, M., Jalali, R., et al. (2019) Recent Developments and Future Directions in Adult Lower-Grade Gliomas: Society for Neu-ro-Oncology (SNO) and European Association of Neuro-Oncology (EANO) Consensus. Neuro-Oncology, 21, 837-853. [Google Scholar] [CrossRef] [PubMed]
[4] Jakola, A.S., Myrmel, K.S., Kloster, R., Torp, S.H., Lindal, S., Unsgard, G. and Solheim, O. (2012) Comparison of a Strategy Favoring Early Surgical Resection vs a Strategy Favoring Watchful Waiting in Low-Grade Gliomas. JAMA, 308, 1881-1888. [Google Scholar] [CrossRef] [PubMed]
[5] Dhawan, S., Patil, C.G., Chen, C. and Venteicher, A.S. (2020) Early Versus Delayed Postoperative Radiotherapy for Treatment of Low-Grade Gliomas. Cochrane Database of Systematic Reviews, No. 1, Article No. CD009229. [Google Scholar] [CrossRef
[6] Nejo, T., Matsushita, H., Karasaki, T., Nomura, M., Saito, K., Tanaka, S., Takayanagi, S., Hana, T., Takahashi, S., Kitagawa, Y., et al. (2019) Reduced Neoantigen Expression Re-vealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma. Cancer Immunology Research, 7, 1148-1161. [Google Scholar] [CrossRef
[7] Appolloni, I., Alessandrini, F., Ceresa, D., Marubbi, D., Gambini, E., Reverberi, D., Loiacono, F. and Malatesta, P. (2019) Progression from Low- to High-Grade in a Glioblas-toma Model Reveals the Pivotal Role of Immunoediting. Cancer Letters, 442, 213-221. [Google Scholar] [CrossRef] [PubMed]
[8] Timpl, R., Rohde, H., Robey, P.G., Rennard, S.I., Foidart, J.M. and Martin, G.R. (1979) Laminin—A Glycoprotein from Basement Membranes. The Journal of Biological Chemistry, 254, 9933-9937. [Google Scholar] [CrossRef
[9] Chung, A.E., Jaffe, R., Freeman, I.L., Vergnes, J.P., Bra-ginski, J.E. and Carlin, B. (1979) Properties of a Basement Membrane-Related Glycoprotein Synthesized in Culture by a Mouse Embryonal Carcinoma-Derived Cell Line. Cell, 16, 277-287. [Google Scholar] [CrossRef] [PubMed]
[10] Aumailley, M., Bruckner-Tuderman, L., Carter, W.G., Deutz-mann, R., Edgar, D., Ekblom, P., Engel, J., Engvall, E., Hohenester, E., Jones, J.C., et al. (2005) A Simplified Laminin Nomenclature. Matrix Biology, 24, 326-332. [Google Scholar] [CrossRef] [PubMed]
[11] Yurchenco, P.D. (2011) Basement Membranes: Cell Scaffold-ings and Signaling Platforms. Cold Spring Harbor Perspectives Biology, 3, a004911. [Google Scholar] [CrossRef] [PubMed]
[12] Qin, Y., Rodin, S., Simonson, O.E. and Hollande, F. (2017) Laminins and Cancer Stem Cells: Partners in Crime? Seminars in Cancer Biology, 45, 3-12. [Google Scholar] [CrossRef] [PubMed]
[13] Korbakis, D., Dimitromanolakis, A., Prassas, I., Davis, G.J., Barber, E., Reckamp, K.L., Blasutig, I. and Diamandis, E.P. (2015) Serum LAMC2 Enhances the Prognostic Value of a Multi-Parametric Panel in Non-Small Cell Lung Cancer. British Journal of Cancer, 113, 484-491. [Google Scholar] [CrossRef] [PubMed]
[14] Bello, L., Giussani, C., Carrabba, G., Pluderi, M., Costa, F. and Bikfalvi, A. (2004) Angiogenesis and Invasion in Gliomas. Cancer Treatment and Research, 117, 263-284. [Google Scholar] [CrossRef] [PubMed]
[15] Onishi, M., Kurozumi, K., Ichikawa, T. and Date, I. (2013) Mechanisms of Tumor Development and Anti-Angiogenic Therapy in Glioblastoma Multiforme. Neurologia Medi-co-Chirurgica, 53, 755-763. [Google Scholar] [CrossRef] [PubMed]
[16] Kurozumi, K., Onishi, M., Ichikawa, T., Fujii, K., Ishida, J., Shima-zu, Y. and Date, I. (2013) [III. Molecular Targeting Therapy for Glioma-Bevacizumab and Cilengitide]. Japanese Journal of Cancer and Chemotherapy, 40, 718-722.
[17] Varner, J.A. and Cheresh, D.A. (1996) Integrins and Cancer. Current Opinion in Cell Biology, 8, 724-730. [Google Scholar] [CrossRef
[18] Lu, P., Weaver, V.M. and Werb, Z. (2012) The Extracellular Matrix: A Dynamic Niche in Cancer Progression. Journal of Cell Biology, 196, 395-406. [Google Scholar] [CrossRef] [PubMed]
[19] Patarroyo, M., Tryggvason, K. and Virtanen, I. (2002) Laminin Isoforms in Tumor Invasion, Angiogenesis and Metastasis. Seminars in Cancer Biology, 12, 197-207. [Google Scholar] [CrossRef
[20] Oikawa, Y., Hansson, J., Sasaki, T., Rousselle, P., Do-mogatskaya, A., Rodin, S., Tryggvason, K. and Patarroyo, M. (2011) Melanoma Cells Produce Multiple Laminin Isoforms and Strongly Migrate on α5 Laminin(s) via Several Integrin Receptors. Experimental Cell Research, 317, 1119-1133. [Google Scholar] [CrossRef] [PubMed]
[21] Givant-Horwitz, V., Davidson, B. and Reich, R. (2004) Laminin-Induced Signaling in Tumor Cells: The Role of the M(r) 67,000 Laminin Receptor. Cancer Research, 64, 3572-3579. [Google Scholar] [CrossRef
[22] Takada, Y., Ye, X. and Simon, S. (2007) The Integrins. Genome Biology, 8, Article No. 215. [Google Scholar] [CrossRef] [PubMed]
[23] Hood, J.D. and Cheresh, D.A. (2002) Role of Integrins in Cell Inva-sion and Migration. Nature Reviews Cancer, 2, 91-100. [Google Scholar] [CrossRef] [PubMed]
[24] Schnell, O., Krebs, B., Wagner, E., Romagna, A., Beer, A.J., Grau, S.J., Thon, N., Goetz, C., Kretzschmar, H.A., Tonn, J.C. and Goldbrunner, R.H. (2008) Expression of Integrin αvβ3 in Gliomas Correlates with Tumor Grade and Is Not Restricted to Tumor Vas-culature. Brain Pathology, 18, 378-386. [Google Scholar] [CrossRef] [PubMed]
[25] Kurozumi, K., Ichikawa, T., Onishi, M., Fujii, K. and Date, I. (2012) Cilengitide Treatment for Malignant Glioma: Current Status and Future Direction. Neurologia Medico-Chirurgica, 52, 539-547. [Google Scholar] [CrossRef] [PubMed]
[26] Meyer, A., Auernheimer, J., Modlinger, A. and Kessler, H. (2006) Targeting RGD Recognizing Integrins: Drug Development, Bio-material Research, Tumor Imaging and Targeting. Current Pharmaceutical Design, 12, 2723-2747. [Google Scholar] [CrossRef] [PubMed]
[27] Leavesley, D.I., Ferguson, G.D., Wayner, E.A. and Cheresh, D.A. (1992) Requirement of the Integrin β3 Subunit for Carcinoma Cell Spreading or Migration on Vitronectin and Fi-brinogen. Journal of Cell Biology, 117, 1101-1107. [Google Scholar] [CrossRef] [PubMed]
[28] Tabatabai, G., Weller, M., Nabors, B., Picard, M., Reardon, D., Mik-kelsen, T., Ruegg, C. and Stupp, R. (2010) Targeting Integrins in Malignant Glioma. Targeted Oncology, 5, 175-181. [Google Scholar] [CrossRef] [PubMed]
[29] MacDonald, T.J., Taga, T., Shimada, H., Tabrizi, P., Zlokovic, B.V., Cheresh, D.A. and Laug, W.E. (2001) Preferential susceptibility of Brain Tumors to the Antiangiogenic Effects of an αv Integrin Antagonist. Neurosurgery, 48, 151-157. [Google Scholar] [CrossRef
[30] Onishi, M., Kurozumi, K., Ichikawa, T., Michiue, H., Fujii, K., Ishida, J., Shimazu, Y., Chiocca, E.A., Kaur, B. and Date, I. (2013) Gene Expression Profiling of the An-ti-Glioma Effect of Cilengitide. SpringerPlus, 2, Article No. 160. [Google Scholar] [CrossRef] [PubMed]