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

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.

Keywords

glioblastoma / microRNAs / microRNA-1224-5p / bioinformatics

References

[1] BleekerFE, MolenaarRJ, LeenstraS. Recent advances in the molecular understanding of glioblastoma. J Neurooncol, 2012, 108(1): 11-27

[2] CrocettiE, TramaA, StillerC, et al.. Epidemiology of glial and non-glial brain tumours in Europe. Eur J Cancer, 2012, 48(10): 1532-1542

[3] OhgakiH, DessenP, JourdeB, et al.. Genetic pathways to glioblastoma: a population-based study. Cancer Res, 2004, 64(19): 6892-6899

[4] StuppR, BradaM, van den BentMJ, et al.. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2014, 25(Suppl 3): iii93-101

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

[6] BingZT, YangGH, XiongJ, 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

[7] KhaddourK, JohannsTM, AnsstasG. The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions. Pharmaceuticals (Basel), 2020, 13(11): 389

[8] SzopaW, BurleyTA, Kramer-MarekG, et al.. Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives. Biomed Res Int, 2017, 2017: 8013575

[9] Lagos-QuintanaM, RauhutR, LendeckelW, et al.. Identification of novel genes coding for small expressed RNAs. Science, 2001, 294(5543): 853-858

[10] O’BrienJ, HayderH, ZayedY, et al.. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne), 2018, 9: 402

[11] TanW, LiuB, QuS, et al.. MicroRNAs and cancer: Key paradigms in molecular therapy. Oncol Lett, 2018, 15(3): 2735-2742

[12] PengY, CroceCM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther, 2016, 1: 15004

[13] Esquela-KerscherA, SlackFJ. Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer, 2006, 6(4): 259-269

[14] WangBC, MaJ. Role of MicroRNAs in Malignant Glioma. Chin Med J (Engl), 2015, 128(9): 1238-1244

[15] SheaA, HarishV, AfzalZ, et al.. MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics. Cancer Med, 2016, 5(8): 1917-1946

[16] QiuS, LinS, HuD, 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

[17] LingN, GuJ, LeiZ, et al.. microRNA-155 regulates cell proliferation and invasion by targeting FOXO3a in glioma. Oncol Rep, 2013, 30(5): 2111-2118

[18] ShangC, HongY, GuoY, et al.. MiR-210 up-regulation inhibits proliferation and induces apoptosis in glioma cells by targeting SIN3A. Med Sci Monit, 2014, 20: 2571-2577

[19] KefasB, GodlewskiJ, ComeauL, 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

[20] CandidoS, LupoG, PennisiM, 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

[21] LiuY, YanW, ZhangW, et al.. MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1. Oncol Rep, 2012, 28(3): 1013-1021

[22] LiuC, GeYY, XieXX, et al.. Identification of Dysregulated microRNAs in Glioma Using RNA-sequencing. Curr Med Sci, 2021, 41(2): 356-367

[23] LoveMI, HuberW, AndersS. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol, 2014, 15(12): 550

[24] HolleczekB, BrennerH. 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

[25] ShannonP, MarkielA, OzierO, et al.. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 2003, 13(11): 2498-2504

[26] FurnariFB, FentonT, BachooRM, et al.. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev, 2007, 21(21): 2683-2710

[27] BartelDP. MicroRNAs: target recognition and regulatory functions. Cell, 2009, 136(2): 215-233

[28] TieJ, FanD. Big roles of microRNAs in tumorigenesis and tumor development. Histol Histopathol, 2011, 26(10): 1353-1361

[29] SiW, ShenJ, ZhengH, et al.. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics, 2019, 11(1): 25

[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] MatosB, BostjancicE, MatjasicA, 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

[32] SilberJ, JamesCD, HodgsonJG. microRNAs in gliomas: small regulators of a big problem. Neuromolecular Med, 2009, 11(3): 208-222

[33] ZhangY, DuttaA, AbounaderR. The role of microRNAs in glioma initiation and progression. Front Biosci (Landmark Ed), 2012, 17: 700-712

[34] PiweckaM, RolleK, BelterA, et al.. Comprehensive analysis of microRNA expression profile in malignant glioma tissues. Mol Oncol, 2015, 9(7): 1324-1340

[35] BrowerJV, ClarkPA, LyonW, et al.. MicroRNAs in cancer: glioblastoma and glioblastoma cancer stem cells. Neurochem Int, 2014, 77: 68-77

[36] PapagiannakopoulosT, ShapiroA, KosikKS. Micro RNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res, 2008, 68(19): 8164-8172

[37] GabrielyG, WurdingerT, KesariS, et al.. MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol, 2008, 28(17): 5369-5380

[38] ZhouX, RenY, MooreL, 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

[39] SeoYE, SuhHW, BahalR, et al.. Nanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma. Biomaterials, 2019, 201: 87-98

[40] BurottoM, ChiouVL, LeeJM, et al.. The MAPK pathway across different malignancies: a new perspective. Cancer, 2014, 120(22): 3446-3456

[41] XinP, XuX, DengC, et al.. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol, 2020, 80: 106210

[42] XiaoF, ChengZ, WangP, 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

[43] LiuJ, LiuXQ, LiuY, 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

[44] ShiX, TengF. 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

[45] WanJ, GuoAA, ChowdhuryI, 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

[46] HanQ, LiJ, XiongJ, 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

[47] NymarkP, GuledM, BorzeI, 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

[48] WangQ, ZhangR, LiuD. 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

[49] ZhuangC, HuangX, YuJ, et al.. Circular RNA hsa_circ_0075828 promotes bladder cancer cell proliferation through activation of CREB1. BMB Rep, 2020, 53(2): 82-87

[50] MosakhaniN, LahtiL, BorzeI, 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

[51] QianJ, LiR, WangYY, 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