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MiR-21, miR-34a, miR-125b, miR-181d and miR-648 levels inversely correlate with MGMT and TP53 expression in primary glioblastoma patients

Dorota Jesionek-Kupnicka, Marcin Braun, Berenika Trąbska-Kluch, Joanna Czech, Małgorzata Szybka, Bożena Szymańska, Dominika Kulczycka-Wojdala, Michał Bieńkowski, Radzisław Kordek, Izabela Zawlik

Arch Med Sci
Online publish date: 2017/07/31
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Introduction: TP53 and MGMT alterations play a crucial role in glioblastoma (GB) pathogenesis. TP53 and MGMT function is affected by several pathologic mechanisms, such as point mutations or promoter methylation, which are well characterized. Expression of both genes can be regulated by other mechanisms as well, e.g., microRNAs (miRNAs). Moreover, cross-talk among various pathologic processes may occur, further affecting MGMT and TP53 functionality.

Material and methods: In 49 GB patients, we analyzed the possible associations between TP53 and its miRNA regulators miR-125b, miR-21, and miR-34a, as well as MGMT and its miRNA regulators miR-181d and miR-648. We evaluated the possible influence of mutational and methylation status on the pre-identified associations.

Results: In patients with immunohistochemistry-detected TP53 overexpression, expression levels of miR-34a and TP53 were negatively correlated (r = –0.56, p = 0.0195), and in patients with TP53 mutations, expression levels of TP53 and miR-21 were negatively correlated (r = –0.67, p = 0.0330). In patients with MGMT methylation, expression levels of MGMT were negatively correlated with miR-648 and miR-125b expression levels (r = –0.61, p = 0.0269 and r = –0.34, p = 0.0727, respectively).

Conclusions: Our findings demonstrate that selected miRNAs are significantly correlated with MGMT and TP53 levels, but the extent of this correlation differs regarding the TP53 and MGMT mutational and promoter methylation status.

GB, MGMT, TP53, O6-methylguanine-DNA methyltransferase, microRNA

Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131: 803-20.
Hong Y, Shi Y, Shang C, et al. Influence of far upstream element binding protein 1 gene on chemotherapy sensitivity in human U251 glioblastoma cells. Arch Med Sci 2016; 12: 156-62.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987-96.
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459-66.
Alifieris C, Trafalis DT. Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther 2015; 152: 63-82.
Vlachostergios PJ, Papandreou CN. Efficacy of low dose temozolomide in combination with bortezomib in U87 glioma cells: a flow cytometric analysis. Arch Med Sci 2015; 11: 307-10.
Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997-1003.
Preusser M, de Ribaupierre S, Wöhrer A, et al. Current concepts and management of glioblastoma. Ann Neurol 2011; 70: 9-21.
Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res 2013; 19: 764-72.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061-8.
Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol 2005; 109: 93-108.
McLendon R, Friedman A, Bigner D, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061-8.
Amatya VJ, Naumann U, Weller M, Ohgaki H. TP53 promoter methylation in human gliomas. Acta Neuropathol 2005; 110: 178-84.
Jesionek-Kupnicka D, Szybka M, Malachowska B, et al. TP53 promoter methylation in primary glioblastoma: relationship with TP53 mRNA and protein expression and mutation status. DNA Cell Biol 2014; 33: 217-26.
Feng Z, Zhang C, Wu R, Hu W. Tumor suppressor p53 meets microRNAs. J Mol Cell Biol 2011; 3: 44-50.
Dunn J, Baborie A, Alam F, et al. Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 2009; 101: 124-31.
Jesien-Lewandowicz E, Jesionek-Kupnicka D, Zawlik I, et al. High incidence of MGMT promoter methylation in primary glioblastomas without correlation with TP53 gene mutations. Cancer Genet Cytogenet 2009; 188: 77-82.
Crinière E, Kaloshi G, Laigle-Donadey F, et al. MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities. J Neurooncol 2007; 83: 173-9.
Kreth S, Limbeck E, Hinske LC, et al. In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing. Acta Neuropathol 2013; 125: 671-81.
Fan YN, Meley D, Pizer B, See V. Mir-34a mimics are potential therapeutic agents for p53-mutated and chemo-resistant brain tumour cells. PLoS One 2014; 9: e108514.
Freeman JA, Espinosa JM. The impact of post-transcriptional regulation in the p53 network. Brief Funct Genomics 2013; 12: 46-57.
Shi L, Zhang S, Feng K, et al. MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis. Int J Oncol 2012; 40: 119-29.
Bradley BS, Loftus JC, Mielke CJ, Dinu V. Differential expression of microRNAs as predictors of glioblastoma phenotypes. BMC Bioinformatics 2014; 15: 21.
Karsy M, Gelbman M, Shah P, Balumbu O, Moy F, Arslan E. Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features. Folia Neuropathol 2012; 50: 301-21.
Dong H, Siu H, Luo L, Fang X, Jin L, Xiong M. Investigating gene and microRNA expression in glioblastoma. BMC Genomics 2009; 11: 17-22.
Chang TC, Wentzel EA, Kent OA, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 2007; 26: 745-52.
He L, He X, Lowe SW, Hannon GJ. Suppression puzzle. Nat Rev Cancer 2007; 7: 819-22.
Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA 2007; 104: 15472-7.
Le MTN, Teh C, Shyh-Chang N, et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev 2009; 23: 862-76.
Haemmig S, Baumgartner U, Glück A, et al. miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas. Cell Death Dis 2014; 5: e1279.
Zhang W, Zhang J, Hoadley K, et al. MiR-181d: predictive glioblastoma biomarker that downregulates MGMT expression. Neuro Oncol 2012; 14: 712-9.
Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114: 97-109.
Nagpal J, Jamoona A, Gulati ND, et al. Revisiting the role of p53 in primary and secondary glioblastomas. Anticancer Res 2006; 26: 4633-9.
Preusser M. MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue. Histol Histopathol 2009; 24: 511-8.
Capper D, Mittelbronn M, Meyermann R, Schittenhelm J. Pitfalls in the assessment of MGMT expression and in its correlation with survival in diffuse astrocytomas: proposal of a feasible immunohistochemical approach. Acta Neuropathol 2008; 115: 249-59.
Yunqing L, Guessous F, Ying Z, et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 2009; 69: 7569-76.
Gao H, Zhao H, Xiang W. Expression level of human miR-34a correlates with glioma grade and prognosis. J Neurooncol 2013; 113: 221-8.
Tsuda H, Hirohashi S. Association among p53 gene mutation, nuclear accumulation of the p53 protein and aggressive phenotypes in breast cancer. Int J Cancer 1994; 57: 498-503.
Esrig D, Spruck CH, Nichols PW, et al. p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol 1993; 143: 1389-97.
Ren F, Zhang X, Liang H, et al. Prognostic significance of MiR-34a in solid tumors: a systemic review and meta-analysis with 4030 patients. Int J Clin Exp Med 2015; 8: 17377-91.
Mraz M, Malinova K, Kotaskova J, et al. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 2009; 23: 1159-63.
Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 2006; 103: 2257-61.
Silber J, Lim DA, Petritsch C, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 2008; 6: 14.
Slaby O, Lakomy R, Fadrus P, et al. MicroRNA-181 family predicts response to concomitant chemoradiotherapy with temozolomide in glioblastoma patients. Neoplasma 2010; 57: 264-9.
Rao SA, Santosh V, Somasundaram K. Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma. Mod Pathol 2010; 23: 1404-17.
Yang CH, Yue J, Pfeffer SR, et al. MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3). J Biol Chem 2014; 289: 25079-87.
Barbano R, Palumbo O, Pasculli B, et al. A miRNA signature for defining aggressive phenotype and prognosis in gliomas. PLoS One 2014; 9: e108950.
Kushwaha D, Ramakrishnan V, Ng K, et al. A genomewide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas. Oncotarget 2014; 5: 4026-39.
Stark AM, van de Bergh J, Hedderich J, Mehdorn HM, Nabavi A. Glioblastoma: clinical characteristics, prognostic factors and survival in 492 patients. Clin Neurol Neurosurg 2012; 114: 840-5.
Filippini G, Falcone C, Boiardi A, et al. Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma. Neuro Oncol 2008; 10: 79-87.
Zawlik I, Vaccarella S, Kita D, Mittelbronn M, Franceschi S, Ohgaki H. Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology 2009; 32: 21-9.
Jesionek-Kupnicka D, Szybka M, Potemski P, et al. Association of loss of heterozygosity with shorter survival in primary glioblastoma patients. Pol J Pathol 2013; 64: 268-75.
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