Skip to main content
Log in

Microrna-1224-5p Is a Potential Prognostic and Therapeutic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Analyses

  • Published:
Current Medical Science Aims and scope Submit manuscript

Abstract

Objective

Glioblastoma (GBM) is the most common, invasive, and malignant primary brain tumor with a poor prognosis and high recurrence rate. It’s known that some microRNAs (miRNAs) which are associated with tumorigenesis and progression can be considered as prognostic and therapeutic targets in tumors including GBM. This study aims to highlight the potential role of the core miRNAs in GBM and their potential use as a prognostic and therapeutic biomarker.

Methods

Differentially expressed miRNAs (DEmiRNAs) were identified in GBM by integrating miRNA-sequencing results and a GBM microarray dataset from the Gene Expression Omnibus (GEO) database through bioinformatics tools. The dysregulated miRNAs were identified by survival analysis through Chinese Glioma Genome Atlas (CGGA). Target genes of the dysregulated miRNAs were predicted on MiRWalk and miRTarBase database. TAM2.0 database, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were used to analyze the function of the dysregulated miRNAs. Subsequently, protein-protein interaction (PPI) network analysis was used to identify the top 20 hub targets of the up-regulated and down-regulated miRNAs, respectively. Then, core miRNAs in GBM were identified by constructing dysregulated miRNA-differentially expressed hub gene networks. Validation of the core miRNAs expression was detected in 41 GBM tissues compared to 8 normal brain tissues. Furthermore, the potential biomarkers were identified by clinical correlation analysis and survival analysis.

Results

Totally, 68 intersecting DEmiRNAs were identified, 40 of which were upregulated and the other 28 miRNAs were downregulated. Two upregulated and 4 downregulated miRNAs showed prognostic significance. Most differentially expressed hub genes were regulated by the miR-28-5p and miR-1224-5p, which were respectively upregulated and downregulated in GBM. The correlation between miR-1224-5p level and recurrence was statistically significant (P=0.011). Survival analysis showed that high miR-28-5p level and high miR-1224-5p level were both associated with better prognosis. Moreover, high miR-1224-5p level was an independent prognosis factor for GBM patients according to the cox regression analysis.

Conclusion

MiRNA-1224-5p could be a potential target for the prognosis and treatment in GBM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. J Neurooncol, 2012,108(1):11–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Crocetti E, Trama A, Stiller C, et al. Epidemiology of glial and non-glial brain tumours in Europe. Eur J Cancer, 2012,48(10):1532–1542

    Article  PubMed  Google Scholar 

  3. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res, 2004,64(19):6892–6899

    Article  CAS  PubMed  Google Scholar 

  4. Stupp R, Brada M, van den Bent MJ, et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2014,25 Suppl 3:iii93–101

    Article  PubMed  Google Scholar 

  5. Lieberman F. Glioblastoma update: molecular biology, diagnosis, treatment, response assessment, and translational clinical trials. F1000Res, 2017,6:1892

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Bing ZT, Yang GH, Xiong J, et al. Identify signature regulatory network for glioblastoma prognosis by integrative mRNA and miRNA co-expression analysis. IET Syst Biol, 2016,10(6):244–251

    Article  PubMed  PubMed Central  Google Scholar 

  7. Khaddour K, Johanns TM, Ansstas G. The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions. Pharmaceuticals (Basel), 2020,13(11):389

    Article  CAS  Google Scholar 

  8. Szopa W, Burley TA, Kramer-Marek G, et al. Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives. Biomed Res Int, 2017, 2017:8013575

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Lagos-Quintana M, Rauhut R, Lendeckel W, et al. Identification of novel genes coding for small expressed RNAs. Science, 2001,294(5543):853–858

    Article  CAS  PubMed  Google Scholar 

  10. O’Brien J, Hayder H, Zayed Y, et al. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne), 2018,9:402

    Article  Google Scholar 

  11. Tan W, Liu B, Qu S, et al. MicroRNAs and cancer: Key paradigms in molecular therapy. Oncol Lett, 2018, 15(3):2735–2742

    PubMed  Google Scholar 

  12. Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther, 2016,1:15004

    Article  PubMed  PubMed Central  Google Scholar 

  13. Esquela-Kerscher A, Slack FJ. Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer, 2006,6(4):259–269

    Article  CAS  PubMed  Google Scholar 

  14. Wang BC, Ma J. Role of MicroRNAs in Malignant Glioma. Chin Med J (Engl), 2015,128(9):1238–1244

    Article  CAS  Google Scholar 

  15. Shea A, Harish V, Afzal Z, et al. MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics. Cancer Med, 2016,5(8):1917–1946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Qiu S, Lin S, Hu D, et al. Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients. J Transl Med, 2013,11:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ling N, Gu J, Lei Z, et al. microRNA-155 regulates cell proliferation and invasion by targeting FOXO3a in glioma. Oncol Rep, 2013,30(5):2111–2118

    Article  CAS  PubMed  Google Scholar 

  18. Shang C, Hong Y, Guo Y, et al. MiR-210 up-regulation inhibits proliferation and induces apoptosis in glioma cells by targeting SIN3A. Med Sci Monit, 2014,20:2571–2577

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kefas B, Godlewski J, Comeau L, et al. microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res, 2008,68(10):3566–3572

    Article  CAS  PubMed  Google Scholar 

  20. Candido S, Lupo G, Pennisi M, et al. The analysis of miRNA expression profiling datasets reveals inverse microRNA patterns in glioblastoma and Alzheimer’s disease. Oncol Rep, 2019,42(3):911–922

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu Y, Yan W, Zhang W, et al. MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1. Oncol Rep, 2012, 28(3):1013–1021

    Article  PubMed  CAS  Google Scholar 

  22. Liu C, Ge YY, Xie XX, et al. Identification of Dysregulated microRNAs in Glioma Using RNA-sequencing. Curr Med Sci, 2021,41(2):356–367

    Article  CAS  PubMed  Google Scholar 

  23. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol, 2014,15(12):550

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Holleczek B, Brenner H. Model based period analysis of absolute and relative survival with R: data preparation, model fitting and derivation of survival estimates. Comput Methods Programs Biomed, 2013, 110(2):192–202

    Article  PubMed  Google Scholar 

  25. Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 2003,13 (11):2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev, 2007,21(21):2683–2710

    Article  CAS  PubMed  Google Scholar 

  27. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell, 2009,136(2):215–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tie J, Fan D. Big roles of microRNAs in tumorigenesis and tumor development. Histol Histopathol, 2011,26 (10):1353–1361

    CAS  PubMed  Google Scholar 

  29. Si W, Shen J, Zheng H, et al. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics, 2019,11(1):25

    Article  PubMed  PubMed Central  Google Scholar 

  30. Reda El Sayed S, Cristante J, Guyon L, et al. MicroRNA Therapeutics in Cancer: Current Advances and Challenges. Cancers (Basel), 2021,13(11)

  31. Matos B, Bostjancic E, Matjasic A, et al. Dynamic expression of 11 miRNAs in 83 consecutive primary and corresponding recurrent glioblastoma: correlation to treatment, time to recurrence, overall survival and MGMT methylation status. Radiol Oncol, 2018,52(4): 422–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Silber J, James CD, Hodgson JG. microRNAs in gliomas: small regulators of a big problem. Neuromolecular Med, 2009,11(3):208–222

    Article  CAS  PubMed  Google Scholar 

  33. Zhang Y, Dutta A, Abounader R. The role of microRNAs in glioma initiation and progression. Front Biosci (Landmark Ed), 2012,17:700–712

    Article  CAS  Google Scholar 

  34. Piwecka M, Rolle K, Belter A, et al. Comprehensive analysis of microRNA expression profile in malignant glioma tissues. Mol Oncol, 2015,9(7):1324–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brower JV, Clark PA, Lyon W, et al. MicroRNAs in cancer: glioblastoma and glioblastoma cancer stem cells. Neurochem Int, 2014,77:68–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Papagiannakopoulos T, Shapiro A, Kosik KS. Micro RNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res, 2008,68 (19):8164–8172

    Article  CAS  PubMed  Google Scholar 

  37. Gabriely G, Wurdinger T, Kesari S, et al. MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol, 2008,28 (17):5369–5380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou X, Ren Y, Moore L, et al. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest, 2010, 90(2):144–155

    Article  CAS  PubMed  Google Scholar 

  39. Seo YE, Suh HW, Bahal R, et al. Nanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma. Biomaterials, 2019,201:87–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Burotto M, Chiou VL, Lee JM, et al. The MAPK pathway across different malignancies: a new perspective. Cancer, 2014,120(22):3446–3456

    Article  CAS  PubMed  Google Scholar 

  41. Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol, 2020,80:106210

    Article  CAS  PubMed  Google Scholar 

  42. Xiao F, Cheng Z, Wang P, et al. MicroRNA-28-5p inhibits the migration and invasion of gastric cancer cells by suppressing AKT phosphorylation. Oncol Lett, 2018,15(6):9777–9785

    PubMed  PubMed Central  Google Scholar 

  43. Liu J, Liu XQ, Liu Y, et al. MicroRNA 28-5p regulates ATP-binding cassette transporter A1 via inhibiting extracellular signal-regulated kinase 2. Mol Med Rep, 2016,13(1):433–440

    Article  CAS  PubMed  Google Scholar 

  44. Shi X, Teng F. Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1). Mol Cell Biochem, 2015,408(1–2):283–293

    Article  CAS  PubMed  Google Scholar 

  45. Wan J, Guo AA, Chowdhury I, et al. TRPM7 Induces Mechanistic Target of Rap1b Through the Downregulation of miR-28-5p in Glioma Proliferation and Invasion. Front Oncol, 2019,9:1413

    Article  PubMed  PubMed Central  Google Scholar 

  46. Han Q, Li J, Xiong J, et al. Long noncoding RNA LINC00514 accelerates pancreatic cancer progression by acting as a ceRNA of miR-28-5p to upregulate Rap1b expression. J Exp Clin Cancer Res, 2020,39(1):151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nymark P, Guled M, Borze I, et al. Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos- and histology-related changes in lung cancer. Genes Chromosomes Cancer, 2011,50(8):585–597

    Article  CAS  PubMed  Google Scholar 

  48. Wang Q, Zhang R, Liu D. Long non-coding RNA ZEB1-AS1 indicates poor prognosis and promotes melanoma progression through targeting miR-1224-5p. Exp Ther Med, 2019,17(1):857–862

    CAS  PubMed  Google Scholar 

  49. Zhuang C, Huang X, Yu J, et al. Circular RNA hsa_circ_0075828 promotes bladder cancer cell proliferation through activation of CREB1. BMB Rep, 2020,53(2):82–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mosakhani N, Lahti L, Borze I, et al. MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF. Cancer Genet, 2012,205(11):545–551

    Article  CAS  PubMed  Google Scholar 

  51. Qian J, Li R, Wang YY, et al. MiR-1224-5p acts as a tumor suppressor by targeting CREB1 in malignant gliomas. Mol Cell Biochem, 2015,403(1–2):33–41

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the professors of Histology and Embryology Department, School of Pre-clinical Medicine, Guangxi Medical University for the help with technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Xiao-xun Xie or Bin Luo.

Additional information

Conflict of Interest Statement

The authors declare no conflict of interest.

This work was supported in part by the National Natural Science Foundation of China (No. 81960453 and No. 81860445), the Natural Science Foundation of Guangxi Province (No. 2018GXNSFAA050151 and No. 2018GXNSFAA281251), the Basic Ability Improvement Project for Young and Middle-aged Teachers in Colleges and Universities of Guangxi (No. 2020KY03039), the Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University) and Ministry of Education (No. GK2018-09, No. GKE 2019-08, and No. GKE-ZZ202006).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wei, X., Zhang, Qm., Liu, C. et al. Microrna-1224-5p Is a Potential Prognostic and Therapeutic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Analyses. CURR MED SCI 42, 584–596 (2022). https://doi.org/10.1007/s11596-022-2593-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-022-2593-5

Key words

Navigation