Abstract
The aim of our study was to clarify the expression and gene copy number levels of protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), which is thought to be a regulator of the p53 protein in meningiomas of all three different WHO grades. Genomic DNA and mRNA were extracted from frozen tissues of meningiomas (WHO grade I, 20 cases; grade II, 17 cases; grade III, 20 cases). For analysis of the mRNA expression and gene dosage level of PPM1D, semiquantitative duplex RT-PCR, real-time RT-PCR, and semiquantitative duplex PCR were performed. We also analyzed several genes which locate near PPM1D in the genomic locus 17q22–24 using semiquantitative duplex RT-PCR. We found that the mean mRNA expression of PPM1D is higher in WHO grade II and III meningiomas than in grade I tumors. This finding is accompanied by moderate gene dosage increases for PPM1D in meningiomas of higher grades. Other genes located in the vicinity of PPM1D also showed mRNA overexpression in single meningioma cases. For these genes, however, no significant expression differences between meningioma grades could be observed. Thus, PPM1D in the chromosomal location 17q22–24 might be the most relevant candidate gene with respect to a potential functional implication in meningioma progression.
Similar content being viewed by others
References
Perry A, Louis D, Scheithauer B et al (2007) Meningiomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) The 2007 WHO classification of tumours of the central nervous system, 4th edn. IARC Press, Lyon, pp 164–172
Perry A, Scheithauer BW, Stafford SL et al (1999) “Malignancy” in meningiomas: a clinicopathologic study of 116 patients, with grading implications. Cancer 85:2046–2056
Weber RG, Bostrom J, Wolter M et al (1997) Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc Natl Acad Sci USA 94:14719–14724
Barski D, Wolter M, Reifenberger G et al (2010) Hypermethylation and transcriptional downregulation of the TIMP3 gene is associated with allelic loss on 22q12.3 and malignancy in meningiomas. Brain Pathol 20:623–631
Clark VE, Erson-Omay EZ, Serin A et al (2013) Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339:1077–1080
Prives C, Hall PA (1999) The p53 pathway. J Pathol 187:112–126
Purvis JE, Karhohs KW, Mock C et al (2012) p53 dynamics control cell fate. Science 336:1440–1444
Abdelzaher E, El-Gendi SM, Yehya A et al (2011) Recurrence of benign meningiomas: predictive value of proliferative index, BCL2, p53, hormonal receptors and HER2 expression. Br J Neurosurg 25:707–713
Aguiar PH, Agner C, Simm R et al (2002) p53 Protein expression in meningiomas—a clinicopathologic study of 55 patients. Neurosurg Rev 25:252–257
Amatya VJ, Takeshima Y, Inai K (2004) Methylation of p14(ARF) gene in meningiomas and its correlation to the p53 expression and mutation. Mod Pathol 17:705–710
Yang SY, Park CK, Park SH et al (2008) Atypical and anaplastic meningiomas: prognostic implications of clinicopathological features. J Neurol Neurosurg Psychiatry 79:574–580
Bostrom J, Meyer-Puttlitz B, Wolter M et al (2001) Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. Am J Pathol 159:661–669
Bulavin DV, Demidov ON, Saito S et al (2002) Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet 31:210–215
Lu X, Nguyen TA, Moon SH et al (2008) The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev 27:123–135
Saito-Ohara F, Imoto I, Inoue J et al (2003) PPM1D is a potential target for 17q gain in neuroblastoma. Cancer Res 63:1876–1883
Hirasawa A, Saito-Ohara F, Inoue J et al (2003) Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Clin Cancer Res 9:1995–2004
van den Boom J, Wolter M, Kuick R et al (2003) Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. Am J Pathol 163:1033–1043
Buschges R, Ichimura K, Weber RG et al (2002) Allelic gain and amplification on the long arm of chromosome 17 in anaplastic meningiomas. Brain Pathol 12:145–153
Yokota J, Yamamoto T, Toyoshima K et al (1986) Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo. Lancet 1:765–767
Sinclair CS, Rowley M, Naderi A et al (2003) The 17q23 amplicon and breast cancer. Breast Cancer Res Treat 78:313–322
Ehrbrecht A, Muller U, Wolter M et al (2006) Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J Pathol 208:554–563
Couch FJ, Wang XY, Wu GJ et al (1999) Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res 59:1408–1411
Jacobs JJ, Keblusek P, Robanus-Maandag E et al (2000) Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet 26:291–299
Cai DX, James CD, Scheithauer BW et al (2001) PS6K amplification characterizes a small subset of anaplastic meningiomas. Am J Clin Pathol 115:213–218
Surace EI, Lusis E, Haipek CA et al (2004) Functional significance of S6K overexpression in meningioma progression. Ann Neurol 56:295–298
Fiscella M, Zhang H, Fan S et al (1997) Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci USA 94:6048–6053
Takekawa M, Adachi M, Nakahata A et al (2000) p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J 19:6517–6526
Takekawa M, Maeda T, Saito H (1998) Protein phosphatase 2Cα inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO J 17:4744–4752
Hanada M, Kobayashi T, Ohnishi M et al (1998) Selective suppression of stress-activated protein kinase pathway by protein phosphatase 2C in mammalian cells. FEBS Lett 437:172–176
Bulavin DV, Phillips C, Nannenga B et al (2004) Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet 36:343–350
Li J, Yang Y, Peng Y et al (2002) Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat Genet 31:133–134
Tan DS, Lambros MB, Rayter S et al (2009) PPM1D is a potential therapeutic target in ovarian clear cell carcinomas. Clin Cancer Res 15:2269–2280
Wang P, Rao J, Yang H et al (2011) Wip1 over-expression correlated with TP53/p14(ARF) pathway disruption in human astrocytomas. J Surg Oncol 104:679–684
Rauta J, Alarmo EL, Kauraniemi P et al (2006) The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Breast Cancer Res Treat 95:257–263
Khan J, Parsa NZ, Harada T et al (1998) Detection of gains and losses in 18 meningiomas by comparative genomic hybridization. Cancer Genet Cytogenet 103:95–100
Yagi H, Chuman Y, Kozakai Y et al (2012) A small molecule inhibitor of p53-inducible protein phosphatase PPM1D. Bioorg Med Chem Lett 22:729–732
Zhang X, Wan G, Mlotshwa S et al (2010) Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway. Cancer Res 70:7176–7186
Kim MS, Kim KH, Lee EH et al (2014) Results of immunohistochemical staining for cell cycle regulators predict the recurrence of atypical meningiomas. J Neurosurg 121:1189–1200
Ellison DW, Lunec J, Gallagher PJ et al (1995) Accumulation of wild-type p53 in meningiomas. Neuropathol Appl Neurobiol 21:136–142
Ohgaki H, Eibl RH, Schwab M et al (1993) Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system. Mol Carcinog 8:74–80
Wang JL, Zhang ZJ, Hartman M et al (1995) Detection of TP53 gene mutation in human meningiomas: a study using immunohistochemistry, polymerase chain reaction/single-strand conformation polymorphism and DNA sequencing techniques on paraffin-embedded samples. Int J Cancer 64:223–228
Zhang L, Chen LH, Wan H et al (2014) Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet 46:726–730
Acknowledgments
The authors are indebted to Dr. Edward Barroga, Associate Professor and Senior Medical Editor from the Department of International Medical Communications of Tokyo Medical University for editing and reviewing the English manuscript. SF would like to thank Professor Haraoka (Department of Neurosurgery, Tokyo Medical University) and Professor Reifenberger (Department of Neuropathology, Heinrich-Heine University) for helpful suggestions in the initiation of the study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest associated with this study.
Rights and permissions
About this article
Cite this article
Fukami, S., Riemenschneider, M.J., Kohno, M. et al. Expression and gene doses changes of the p53-regulator PPM1D in meningiomas: a role in meningioma progression?. Brain Tumor Pathol 33, 191–199 (2016). https://doi.org/10.1007/s10014-016-0252-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10014-016-0252-x