RELB: A novel prognostic marker for glioblastoma as identified by population‑based analysis

Zeng,Fan; Wang,Kuanyu; Huang,Ruoyu; Liu,Yanwei; Zhang,Ying; Hu,Huimin

doi:10.3892/ol.2019.10296

RELB: A novel prognostic marker for glioblastoma as identified by population‑based analysis

Authors:
- Fan Zeng
- Kuanyu Wang
- Ruoyu Huang
- Yanwei Liu
- Ying Zhang
- Huimin Hu
View Affiliations

Affiliations: Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China, Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China, Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, P.R. China
Published online on: April 30, 2019 https://doi.org/10.3892/ol.2019.10296
Pages: 386-394
Copyright: © Zeng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant type of glioma, with a poor prognosis for patients. The survival time of patients varies greatly due to the complexity of the human genome, which harbors diverse oncogenic drivers. In order to identify the specific driving factors, 325 glioma samples from the Chinese Glioma Genome Atlas (CGGA) database were analyzed in the present study. The level of RELB proto‑oncogene, NF‑κβ subunit (RELB) expression increased with the pathological grade progression of the gliomas, and higher expression levels were present in the mesenchymal subtype and isocitrate dehydrogenase 1 (IDH1) wild‑type gliomas. This RELB expression pattern was identified in the CGGA database and observed in three large independent databases. In patients with GBM from the CGGA database, a higher RELB expression level was associated with a shorter survival time, a mesenchymal subtype and IDH1 wild‑type gliomas. Kaplan‑Meier survival analysis, survival nomograms and Cox analysis demonstrated an independent prognostic value for RELB expression. Moreover, biological function analysis indicated the association of RELB with the ‘immune response’, ‘cell activation’ and the ‘apoptotic process’. In addition, RELB expression levels exhibited a negative correlation with the levels of microRNA (miR)‑139‑5p and miR‑139‑3p. The present study identified the pathological and biological roles of RELB in glioma and revealed its independent prognostic effect. These results suggested that RELB may be used as a prognostic biomarker and potential therapeutic target in glioma.

View Figures

View References

1	Louis DN: Molecular pathology of malignant gliomas. Annu Rev Pathol. 1:97–117. 2006. View Article : Google Scholar : PubMed/NCBI
2	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
3	Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK and DePinho RA: Malignant glioma: Genetics and biology of a grave matter. Genes Dev. 15:1311–1333. 2001. View Article : Google Scholar : PubMed/NCBI
4	Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, et al: CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett. 375:263–273. 2016. View Article : Google Scholar : PubMed/NCBI
5	Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, Kang C, You Y, Jiang C, Song SW, et al: miR-181d: A predictive glioblastoma biomarker that downregulates MGMT expression. Neuro Oncol. 14:712–719. 2012. View Article : Google Scholar : PubMed/NCBI
6	Bao ZS, Chen HM, Yang MY, Zhang CB, Yu K, Ye WL, Hu BQ, Yan W, Zhang W, Akers J, et al: RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res. 24:1765–1773. 2014. View Article : Google Scholar : PubMed/NCBI
7	Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med. 360:765–773. 2009. View Article : Google Scholar : PubMed/NCBI
8	Hayden MS and Ghosh S: NF-κB, the first quarter-century: Remarkable progress and outstanding questions. Genes Dev. 26:203–234. 2012. View Article : Google Scholar : PubMed/NCBI
9	Baud V and Collares D: Post-translational modifications of RelB NF-κB subunit and associated functions. Cells. 5(pii): E222016. View Article : Google Scholar : PubMed/NCBI
10	Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD, et al: Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 24:331–346. 2013. View Article : Google Scholar : PubMed/NCBI
11	Raychaudhuri B, Han Y, Lu T and Vogelbaum MA: Aberrant constitutive activation of nuclear factor kappaB in glioblastoma multiforme drives invasive phenotype. J Neurooncol. 85:39–47. 2007. View Article : Google Scholar : PubMed/NCBI
12	Lopez-Guerra M and Colomer D: NF-kappaB as a therapeutic target in chronic lymphocytic leukemia. Expert Opin Ther Targets. 14:275–288. 2010. View Article : Google Scholar : PubMed/NCBI
13	Sun SC: Non-canonical NF-κB signaling pathway. Cell Res. 21:71–85. 2011. View Article : Google Scholar : PubMed/NCBI
14	Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F, Chalbos D and Sonenshein GE: Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol. 9:470–478. 2007. View Article : Google Scholar : PubMed/NCBI
15	Hu H, Wang Z, Liu Y, Zhang C, Li M, Zhang W, Wang K, Cai J, Cheng W, Huang H and Jiang T: Genome-wide transcriptional analyses of Chinese patients reveal cell migration is attenuated in IDH1-mutant glioblastomas. Cancer Lett. 357:566–574. 2015. View Article : Google Scholar : PubMed/NCBI
16	Sun Y, Zhang W, Chen D, Lv Y, Zheng J, Lilljebjörn H, Ran L, Bao Z, Soneson C, Sjögren HO, et al: A glioma classification scheme based on coexpression modules of EGFR and PDGFRA. Proc Natl Acad Sci USA. 111:3538–3543. 2014. View Article : Google Scholar : PubMed/NCBI
17	Wang Z, Zhang C, Liu X, Wang Z, Sun L, Li G, Liang J, Hu H, Liu Y, Zhang W and Jiang T: Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. Oncoimmunology. 5:e11963102016. View Article : Google Scholar : PubMed/NCBI
18	Gu Z, Gu L, Eils R, Schlesner M and Brors B: Circlize implements and enhances circular visualization in R. Bioinformatics. 30:2811–2812. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zhang ZL, Zhao LJ, Chai L, Zhou SH, Wang F, Wei Y, Xu YP and Zhao P: Seven LncRNA-mRNA based risk score predicts the survival of head and neck squamous cell carcinoma. Sci Rep. 7:3092017. View Article : Google Scholar : PubMed/NCBI
20	Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, et al: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 17:98–110. 2010. View Article : Google Scholar : PubMed/NCBI
21	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI
22	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
23	Park JY and Nam JH: Progestins in the fertility-sparing treatment and retreatment of patients with primary and recurrent endometrial cancer. Oncologist. 20:270–278. 2015. View Article : Google Scholar : PubMed/NCBI
24	Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D, Tizard R, Cate R and Lo D: Expression of relB is required for the development of thymic medulla and dendritic cells. Nature. 373:531–536. 1995. View Article : Google Scholar : PubMed/NCBI
25	Baud V and Jacque E: The alternative NF-kB activation pathway and cancer: Friend or foe? Med Sci (Paris). 24:1083–1088. 2008.(In French). View Article : Google Scholar : PubMed/NCBI
26	Mineva ND, Wang X, Yang S, Ying H, Xiao ZX, Holick MF and Sonenshein GE: Inhibition of RelB by 1,25-dihydroxyvitamin D3 promotes sensitivity of breast cancer cells to radiation. J Cell Physiol. 220:593–599. 2009. View Article : Google Scholar : PubMed/NCBI
27	Demicco EG, Kavanagh KT, Romieu-Mourez R, Wang X, Shin SR, Landesman-Bollag E, Seldin DC and Sonenshein GE: RelB/p52 NF-kappaB complexes rescue an early delay in mammary gland development in transgenic mice with targeted superrepressor IkappaB-alpha expression and promote carcinogenesis of the mammary gland. Mol Cell Biol. 25:10136–10147. 2005. View Article : Google Scholar : PubMed/NCBI
28	Xu Y, Josson S, Fang F, Oberley TD, St Clair DK, Wan XS, Sun Y, Bakthavatchalu V, Muthuswamy A and St Clair WH: RelB enhances prostate cancer growth: Implications for the role of the nuclear factor-kappaB alternative pathway in tumorigenicity. Cancer Res. 69:3267–3271. 2009. View Article : Google Scholar : PubMed/NCBI
29	Josson S, Xu Y, Fang F, Dhar SK, St Clair DK and St Clair WH: RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells. Oncogene. 25:1554–1559. 2006. View Article : Google Scholar : PubMed/NCBI
30	Lee DW, Ramakrishnan D, Valenta J, Parney IF, Bayless KJ and Sitcheran R: The NF-κB RelB protein is an oncogenic driver of mesenchymal glioma. PLoS One. 8:e574892013. View Article : Google Scholar : PubMed/NCBI
31	Cherry EM, Lee DW, Jung JU and Sitcheran R: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioma cell invasion through induction of NF-κB-inducing kinase (NIK) and noncanonical NF-κB signaling. Mol Cancer. 14:92015. View Article : Google Scholar : PubMed/NCBI
32	Cormier F, Monjanel H, Fabre C, Billot K, Sapharikas E, Chereau F, Bordereaux D, Molina TJ, Avet-Loiseau H and Baud V: Frequent engagement of RelB activation is critical for cell survival in multiple myeloma. PLoS One. 8:e591272013. View Article : Google Scholar : PubMed/NCBI
33	Ge QL, Liu SH, Ai ZH, Tao MF, Ma L, Wen SY, Dai M, Liu F, Liu HS, Jiang RZ, et al: RelB/NF-κB links cell cycle transition and apoptosis to endometrioid adenocarcinoma tumorigenesis. Cell Death Dis. 7:e24022016. View Article : Google Scholar : PubMed/NCBI
34	Vallabhapurapu S and Karin M: Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 27:693–733. 2009. View Article : Google Scholar : PubMed/NCBI
35	Baldwin AS: Regulation of cell death and autophagy by IKK and NF-κB: Critical mechanisms in immune function and cancer. Immunol Rev. 246:327–345. 2012. View Article : Google Scholar : PubMed/NCBI
36	Vogel CF, Wu D, Goth SR, Baek J, Lollies A, Domhardt R, Grindel A and Pessah IN: Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation. Immunol Cell Biol. 91:568–575. 2013. View Article : Google Scholar : PubMed/NCBI
37	Zhu HC, Qiu T, Liu XH, Dong WC, Weng XD, Hu CH, Kuang YL, Gao RH, Dan C and Tao T: Tolerogenic dendritic cells generated by RelB silencing using shRNA prevent acute rejection. Cell Immunol. 274:12–18. 2012. View Article : Google Scholar : PubMed/NCBI
38	Lu L, Bai Y and Wang Z: Elevated T cell activation score is associated with improved survival of breast cancer. Breast Cancer Res Treat. 164:689–696. 2017. View Article : Google Scholar : PubMed/NCBI
39	Carthew RW and Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs. Cell. 136:642–655. 2009. View Article : Google Scholar : PubMed/NCBI
40	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
41	Jansson MD and Lund AH: MicroRNA and cancer. Mol Oncol. 6:590–610. 2012. View Article : Google Scholar : PubMed/NCBI
42	Sun C, Sang M, Li S, Sun X, Yang C, Xi Y, Wang L, Zhang F, Bi Y, Fu Y and Li D: Hsa-miR-139-5p inhibits proliferation and causes apoptosis associated with down-regulation of c-Met. Oncotarget. 6:39756–39792. 2015. View Article : Google Scholar : PubMed/NCBI
43	Wong CC, Wong CM, Tung EK, Au SL, Lee JM, Poon RT, Man K and Ng IO: The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology. 140:322–331. 2011. View Article : Google Scholar : PubMed/NCBI
44	Wang K, Jin J, Ma T and Zhai H: miR-139-5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9. J Cell Mol Med. 21:3730–3740. 2017. View Article : Google Scholar : PubMed/NCBI
45	Liu X, Duan B, Dong Y, He C, Zhou H, Sheng H, Gao H and Zhang X: MicroRNA-139-3p indicates a poor prognosis of colon cancer. Int J Clin Exp Pathol. 7:8046–8052. 2014.PubMed/NCBI
46	Wang M, Wen TF, He LH, Li C, Zhu WJ and Trishul NM: A six-microRNA set as prognostic indicators for bile duct cancer. Int J Clin Exp Med. 8:17261–17270. 2015.PubMed/NCBI
47	Huang P, Xi J and Liu S: miR-139-3p induces cell apoptosis and inhibits metastasis of cervical cancer by targeting NOB1. Biomed Pharmacother. 83:850–856. 2016. View Article : Google Scholar : PubMed/NCBI