J Korean Neurosurg Soc.  2025 Mar;68(2):184-201. 10.3340/jkns.2024.0106.

BIRC5 Is a Potential Biomarker Associated with Immune System Infiltration in Glioma

• Yang X
• Zhang Y
• Duan F
• Li S
• Wang G

• KMID: 2565276
• DOI: http://doi.org/10.3340/jkns.2024.0106

Abstract

Objective
: Baculovirus inhibitory of apoptosis repeat-containing 5 (BIRC5) is critically implicated in various types of tumors. However, the specific mechanisms by which it operates in glioma are yet to be fully understood.
Methods
: The data sourced from The Cancer Genome Atlas and Gene Expression Omnibus were merged and analyzed using the R software to investigate the relationship between BIRC5 expression and prognosis and diagnosis outcomes. This exploration was conducted utilizing various biological information repositories. The correlation between BIRC5 and immunity was obtained based on TIMER and TISIDB databases.
Results
: Gliomas displayed a markedly elevated level of BIRC5 expression compared to adjacent tissues. Patients with glioma who exhibit elevated levels of BIRC5 experience poorer prognoses and shorter survival times. Subgroup classification further revealed that heightened expression of BIRC5 led to diminished overall survival. Analysis of logistic regression and COX indicated that expression of BIRC5 serves as a risk factor in glioma development. Functional enrichment pathways showed that the 72 hub genes related to BIRC5 were mainly closely related to nuclear division, spindle, tubulin binding, and cell cycle in glioma patients. BBIRC5 methylation suggested that BIRC5 might influence the immune response regulation and the tumor microenvironment within gliomas. BIRC5 is associated with many chemicals. Additionally, studies conducted using cell experiments and pathological sections have consistently shown that BIRC5 expression is higher in tumor cells compared to normal cells and tissues.
Conclusion
: BIRC5 holds promise as a valuable tool in the diagnosis, prognosis, and management of gliomas.

Keyword

Glioma; BIRC5; Survival; Biomarkers; Immunotherapy

Figure

• 

  Fig. 1. A : Comparisons drawn from The Cancer Genome Atlas (TCGA) database display varying levels of Baculovirus inhibitory of apoptosis repeatcontaining 5 (BIRC5) expression in different cancer datasets compared to normal tissues, suggesting either an upregulation or downregulation in expression levels. B : The expression level of BIRC5 was investigated in both normal tissues and adjacent tissues. C-E : Analyzing tumor tissues from patients with different clinical features within TCGA. F : The expression of BIRC5 in tumor tissues and unpaired para-carcinoma tissues was analyzed utilizing the GSE4290 datasets available in the Gene Expression Omnibus (GEO) database. G : The GSE4290 datasets from the GEO database were utilized to assess BIRC5 expression levels in both tumor tissues and the paired adjacent tissues. *p<0.05, ***p<0.001. TPM : transcripts per million, ACC : adrenocortical carcinoma, BLCA : bladder cancer, BRCA : breast cancer, CESC : cervical squamous cell carcinoma, CHOL : cholangiocarcinoma, COAD : colon adenocarcinoma, DLBC : diffuse large B-cell lymphoma, ESCA : esophageal carcinoma, GBM : glioblastoma multiforme, HNSC : head and neck squamous cell carcinoma, KICH : kidney chromophobe, KIRC : kidney renal clear cell carcinoma, KIRP : kidney renal papillary cell carcinoma, LAML : acute myeloid leukemia, LGG : low grade glioma, LIHC : liver hepatocellular carcinoma, LUAD : lung adenocarcinoma, LUSC : lung squamous cell carcinoma, MESO : malignant mesothelioma, OV : ovarian cancer, PAAD : pancreatic adenocarcinoma, PCPG : pheochromocytoma and paraganglioma, PRAD : prostate adenocarcinoma, READ : rectal adenocarcinoma, SARC : sarcoma, SKCM : skin cutaneous melanoma, STAD : stomach adenocarcinoma, TGCT : testicular germ cell tumor, THCA : thyroid cancer, THYM : thymoma, UCEC : uterine corpus endometrial carcinoma, UCS : uterine carcinosarcoma, UVM : uveal melanoma, OS : overall survival.

• 

  Fig. 2. Survival curves following the Kaplan-Meier method were employed to assess the predictive value of Baculovirus inhibitory of apoptosis repeat-containing 5 (BIRC5) expression levels in glioma, utilizing data from The Cancer Genome Atlas (TCGA). A : The survival analysis overall survival in the glioma patient of TCGA. B : The survival analysis disease specific probabilities in the glioma patient of TCGA. C : Subgroup analysis for World Health Organization (WHO) G2, G3, G4. D : Subgroup analysis for WHO G3, G4. E and F : Subgroup analysis for histological type. G : Subgroup analysis for 1p/19q codeletion. H : Subgroup analysis for primary therapy outcome. I : Subgroup analysis for gender. HR : hazard ratio, PD : progressive disease, SD : stable disease.

• 

  Fig. 3. Assessment of Baculovirus inhibitory of apoptosis repeat-containing 5 (BIRC5) expression’s diagnostic significance in glioma. A : Analysis of the receiver operating characteristic (ROC) curve for BIRC5 in glioma and neighboring tissues. B : ROC curve analysis based on time-dependent survival to predict the survival rates at 1-year, 5-year, and 10-year intervals for BIRC5 expression in glioma and neighboring tissues. C : Nomogram chart for predicting the overall survival rates at 1, 5, and 10 years. D : Assessment of the overall survival prediction model accuracy using the calibration chart. TPR : true positive rate, CI : confidence interval, WHO : World Health Organization, IDH : isocitrate dehydrogenase, Mut : mutant, WT : widetype, CR : complete response, PR : partial response, SD : stable disease, PD : progressive disease.

• 

  Fig. 4. Analysis of functional clustering and interactions among genes related to Baculovirus inhibitory of apoptosis repeat-containing 5 (BIRC5) in glioma. A : A heat map demonstrates the top 30 genes that exhibit positive and negative correlations with BIRC5. The color red is used to represent genes that exhibit positive correlations, whereas the color blue is used for genes showing negative correlations. B : Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to explore BIRC5-related genes in glioma. C : A venn diagram was constructed to include genes associated with BIRC5 and genes related to survival. D : Analysis the GO terms and KEGG pathway of both BIRC5-related and survival-related 72 interaction genes. E : Gene co-expression matrix to further understand the relationships among these genes. UBE2C : ubiquitinconjugating enzyme E2C, AURKB : aurora kinase B, PIMREG : PICALM interacting mitotic regulator gene, CDC25C : cell division cycle 25C, PBK : PDZ binding kinase, CENPA: centromere protein A, HJURP : holliday junction recognition protein, PRM2 : protamine 2, SPC24 : spindle component 24, MELK : maternal embryonic leucine zipper kinase, SGO1 : shugoshin 1, TROAp : trophinin-associated protein, CBX7 : chromobox protein homolog 7, ALDH2 : aldehyde dehydrogenase 2, IGIP : IgA-inducing peptide, LDHD : lactatedehydrogenase D, NRG3 : neuregulin 3, NDRG2 : N-myc downstream regulated gene 2, HPSE2 : heparinase 2, ETNPPL : ethanolamine-phosphate phospho-lyase, WASF3 : Wiskott-Aldrich syndrome protein family member 3, MTURN : maturin neural progenitor differentiation regulator protein homolog, ADARB2 : adenosine deaminase RNA specific B2, HLF : hepatic leukemia factor, NEBL : nebulette, GABRG1 : gamma-amino butyric acid type A receptor gamma1 subunit, BP : biological process, CC : cellular component, MF : molecular function, ARF5 : ADP ribosylation factor 5, AK2 : adenylate kinase 2, CIAPIN : cytokine-induced apoptosis inhibitor 1, DBF4 : dumbbell former 4, ST7L : suppression of tumorigenicity 7-like, ZNF207 : zinc finger protein 207, NCAPD2 : non-SMC condensin I complex subunit D2, ZNF200 : zinc finger protein 200, UTP18 : U3 small nucleolar RNA-as sociated protein 18 homolog, PTBP1 : polypyrimidine tract binding protein 1, BRCA1 : breast cancer susceptibility gene 1, PSMC4 : proteasome 26S subunit ATPase 4, SLC25A39 : solute carrier family 25 member 39, TACC3 : transforming acidic coiled-coil containing 3, POLA2 : DNA polymerase alpha 2, DEPDC1 : DEP domain containing 1, BAK1 : brassinosteroid insensitive 1-associated kinase 1, TMSB10 : thymosin β10, FAM136A : family with sequence similarity 136 member A, DEPDC1B : DEP domain containing 1B, RPL26L1 : ribosomal protein L26-like 1, METTL1 : methyltransferase like-1 protein, PSMA4 : proteasome 20S subunit alpha 4, TDP1 : tyrosyl-DNA phosphodiesterase 1, TSPAN17: tetraspanin 17, NOP16 : nucleolar protein 16, RFC2 : replication factor C subunit 2.

• 

  Fig. 5. A : Analyzing the proportions of 24 different immune cells and their correlation with Baculovirus inhibitory of apoptosis repeatcontaining 5 (BIRC5) levels. The size of the dots indicates the strength of the Spearman R coefficient. B and C : the connection between infiltration levels of Th2 cells and TFH cells with BIRC5 expression. D : An analysis of the relationship between BIRC5 and chemokines in tumors was presented using a heatmap. E : The connection between the methylation status of BIRC5 and chemokine receptors in tumors. F : The correlation between BIRC5 and immunoinhibitors molecules was revealed through heatmap analysis. G : Heatmap analysis depicted the relationship between BIRC5 and immunostimulators. **p<0.01, ***p<0.001. Th2 : T helper 2, aDC : antigen-specific dendritic cell, iDC : immature dendritic cells, NK : natural killer, CD56dim : CD56 diminutive, TReg : regulatory T cells, pDC : plasmacytoid dendritic cell, Tcm : central memory T cells, TFH : T follicular helper cells.

• 

  Fig. 6. A : The levels of relative messenger RNA (mRNA) of Baculovirus inhibitory of apoptosis repeat-containing 5 (BIRC5) in U251 and human astrocytes (HA) cells were measured through quantitative real-time polymerase chain reaction. B : The BIRC5 protein levels were assessed using Western blot analysis. C : Hematoxylin and Eosin (H&E) staining (×100) and BIRC5 immunohistochemical (IHC) staining (×200) were performed on both normal brain tissue and glioma samples. ****p<0.0001.

Reference

References

1. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 3:917–921. 1997.

2. Cai C, Wang W, Tu Z. Aberrantly DNA methylated-differentially expressed genes and pathways in hepatocellular carcinoma. J Cancer. 10:355–366. 2019.

3. Cao Y, Zhu W, Chen W, Wu J, Hou G, Li Y. Prognostic value of BIRC5 in lung adenocarcinoma lacking EGFR, KRAS, and ALK mutations by integrated bioinformatics analysis. Dis Markers. 2019:5451290. 2019.

4. Cho M, Lee OH, Chang EM, Lee S, Moon S, Lee J, et al. BIRC5 expression is regulated in uterine epithelium during the estrous cycle. Genes (Basel). 11:282. 2020.

5. Conde M, Michen S, Wiedemuth R, Klink B, Schröck E, Schackert G, et al. Chromosomal instability induced by increased BIRC5/survivin levels affects tumorigenicity of glioma cells. BMC Cancer. 17:889. 2017.

6. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 124:263–266. 2006.

7. Davis ME. Epidemiology and overview of gliomas. Semin Oncol Nurs. 34:420–429. 2018.

8. Fecci PE, Sampson JH. The current state of immunotherapy for gliomas: an eye toward the future. J Neurosurg. 131:657–666. 2019.

9. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem. 277:3247–3257. 2002.

10. Ishihara M, Yamamoto K, Miwa H, Nishi M. Spontaneous complete regression of a brain stem glioma pathologically diagnosed as a high-grade glioma. Childs Nerv Syst. 33:2177–2180. 2017.

11. Kamran N, Alghamri MS, Nunez FJ, Shah D, Asad AS, Candolfi M, et al. Current state and future prospects of immunotherapy for glioma. Immunotherapy. 10:317–339. 2018.

12. Li F, Aljahdali I, Ling X. Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study? J Exp Clin Cancer Res. 38:368. 2019.

13. Li K, Lu D, Guo Y, Wang C, Liu X, Liu Y, et al. Trends and patterns of incidence of diffuse glioma in adults in the United States, 1973-2014. Cancer Med. 7:5281–5290. 2018.

14. Lin TY, Chan HH, Chen SH, Sarvagalla S, Chen PS, Coumar MS, et al. BIRC5/survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy. 16:1296–1313. 2020.

15. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 23:1231–1251. 2021.

16. MacDonald JA, Kura N, Sussman C, Woods DC. Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5. J Ovarian Res. 11:89. 2018.

17. McBain C, Lawrie TA, Rogozińska E, Kernohan A, Robinson T, Jefferies S. Treatment options for progression or recurrence of glioblastoma: a network meta-analysis. Cochrane Database Syst Rev. 5:CD013579. 2021.

18. Meder L, König K, Ozretić L, Schultheis AM, Ueckeroth F, Ade CP, et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer. 138:927–938. 2016.

19. Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53- dependent apoptotic pathway. Oncogene. 21:2613–2622. 2002.

20. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Neuro Oncol. 20:iv1–iv86. 2018.

21. Rao S, Kanuri NN, Nimbalkar V, Arivazhagan A, Santosh V. High frequency of H3K27M immunopositivity in adult thalamic glioblastoma. Neuropathology. 39:78–84. 2019.

22. Rosa J, Canovas P, Islam A, Altieri DC, Doxsey SJ. Survivin modulates microtubule dynamics and nucleation throughout the cell cycle. Mol Biol Cell. 17:1483–1493. 2006.

23. Schimmer AD. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res. 64:7183–7190. 2004.

24. Shi J, Tan SY, Lee AZE, Zhang S, Sasidharan SL, Wong B, et al. Restoring apoptosis dysregulation using survivin inhibitor in nasopharyngeal cancer. Head Neck. 42:913–923. 2020.

25. Sowers JL, Johnson KM, Conrad C, Patterson JT, Sowers LC. The role of inflammation in brain cancer. Adv Exp Med Biol. 816:75–105. 2014.

26. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.

27. Varughese RK, Torp SH. Survivin and gliomas: a literature review. Oncol Lett. 12:1679–1686. 2016.

28. Wang N, Huang X, Cheng J. BIRC5 promotes cancer progression and predicts prognosis in laryngeal squamous cell carcinoma. PeerJ. 10:e12871. 2022.

29. Wen PY, Reardon DA. Neuro-oncology in 2015: progress in glioma diagnosis, classification and treatment. Nat Rev Neurol. 12:69–70. 2016.

30. Xu L, Yu W, Xiao H, Lin K. BIRC5 is a prognostic biomarker associated with tumor immune cell infiltration. Sci Rep. 11:390. 2021.

31. Yan X, Su H. YM155 down-regulates survivin and induces P53 up-regulated modulator of apoptosis (PUMA)-dependent in oral squamous cell carcinoma cells. Med Sci Monit. 23:1963–1972. 2017.

32. Ye HB, Ma BJ, Meng GQ, Tao S, Wang Y, Chen Z, et al. Bioinformatics analysis of BIRC5 in human cancers. Ann Transl Med. 10:888. 2022.

33. Zhou M, Gu L, Li F, Zhu Y, Woods WG, Findley HW. DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. J Pharmacol Exp Ther. 303:124–131. 2002.