(Pro)renin receptor is crucial for glioma development via the Wnt/β-catenin signaling pathway

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OBJECTIVE

The (pro)renin receptor (PRR) plays an essential role in the early development of the central nervous system by activating the Wnt/β-catenin signaling pathway. The authors investigated the potential role of the PRR in the pathogenesis of glioma.

METHODS

The authors performed immunohistochemical analysis to detect both the PRR and isocitrate dehydrogenase 1 with mutations involving arginine 132 (IDH1R132H) in paraffin sections of 31 gliomas. Expression of the PRR and Wnt pathway components in cultured human glioma cell lines (U251MG, U87MG, and T98G) was measured using Western blotting. The effects of PRR short interfering RNA (siRNA) on glioma cell proliferation (WST-1 assay and direct cell counting) and apoptosis (flow cytometry and the caspase-3 assay) were also examined.

RESULTS

PRR expression was significantly higher in glioblastoma than in normal tissue or in lower grade glioma, regardless of IDH1R132H mutation. PRR expression was also higher in human glioblastoma cell lines than in human astrocytes. PRR expression showed a significant positive correlation with the Ki-67 labeling index, while it had a significant negative correlation with the survival time of glioma patients. Treatment with PRR siRNA significantly reduced expression of Wnt2, activated β-catenin, and cyclin D1 by human glioblastoma cell lines, and it reduced the proliferative capacity of these cell lines and induced apoptosis.

CONCLUSIONS

This is the first evidence that the PRR has an important role in development of glioma by aberrant activation of the Wnt/β-catenin signaling pathway. This receptor may be both a prognostic marker and a therapeutic target for glioma.

ABBREVIATIONS DAB = 3,3′-diaminobenzidine; FITC = fluorescein isothiocyanate; GBM = glioblastoma; GSC = glioma stem cell; IDH1 = isocitrate dehydrogenase 1; IgG = immunoglobulin G; IHC = immunohistochemical; PBS = phosphate-buffered saline; PI = propidium iodide; PRR = (pro)renin receptor; siRNA = short interfering RNA; V-ATPase = vacuolar H+-adenosine triphosphatase.
Article Information

Contributor Notes

Correspondence Masaaki Kouchi, Department of Neurological Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. email: mkouchi@med.kagawa-u.ac.jp.INCLUDE WHEN CITING Published online January 6, 2017; DOI: 10.3171/2016.9.JNS16431.Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© Copyright 1944-2019 American Association of Neurological Surgeons

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References
  • 1

    Alexson TOHitoshi SColes BLBernstein Avan der Kooy D: Notch signaling is required to maintain all neural stem cell populations—irrespective of spatial or temporal niche. Dev Neurosci 28:34482006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Chen JRYao YXu HZQin ZY: Isocitrate dehydrogenase (IDH)1/2 mutations as prognostic markers in patients with glioblastomas. Medicine (Baltimore) 95:e25832016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chen WJHe DSTang RXRen FHChen G: Ki-67 is a valuable prognostic factor in gliomas: evidence from a systematic review and meta-analysis. Asian Pac J Cancer Prev 16:4114202015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Chiche JBrahimi-Horn MCPouysségur J: Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 14:7717942010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Contrepas AWalker JKoulakoff AFranek KJQadri FGiaume C: A role of the (pro)renin receptor in neuronal cell differentiation. Am J Physiol Regul Integr Comp Physiol 297:R250R2572009

    • Search Google Scholar
    • Export Citation
  • 6

    Cruciat CMOhkawara BAcebron SPKaraulanov EReinhard CIngelfinger D: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327:4594632010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Di Cristofori AFerrero SBertolini IGaudioso GRusso MVBerno V: The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma. Oncotarget 6:17514175312015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Faigle RSong H: Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim Biophys Acta 1830:243524482013

  • 9

    Hemmati HDNakano ILazareff JAMasterman-Smith MGeschwind DHBronner-Fraser M: Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100:15178151832003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Hirose TMori NTotsune KMorimoto RMaejima TKawamura T: Gene expression of (pro)renin receptor is upregulated in hearts and kidneys of rats with congestive heart failure. Peptides 30:231623222009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Ichimura KPearson DMKocialkowski SBäcklund LMChan RJones DT: IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 11:3413472009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Ignatova TNKukekov VGLaywell EDSuslov ONVrionis FDSteindler DA: Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:1932062002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Japan Neurological Society: Report of Brain Tumor Registry of Japan (1984–2000). Neurol Med Chir (Tokyo) 49:SupplPS1PS962009

  • 14

    Johannessen ALTorp SH: The clinical value of Ki-67/MIB-1 labeling index in human astrocytomas. Pathol Oncol Res 12:1431472006

  • 15

    Kim KHSeol HJKim EHRheey JJin HJLee Y: Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells. Neuro Oncol 15:1611712013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Koopman GReutelingsperger CPKuijten GAKeehnen RMPals STvan Oers MH: Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84:141514201994

    • Search Google Scholar
    • Export Citation
  • 17

    Kulshrestha AKatara GKIbrahim SPamarthy SJaiswal MKGilman Sachs A: Vacuolar ATPase ‘a2’ isoform exhibits distinct cell surface accumulation and modulates matrix metalloproteinase activity in ovarian cancer. Oncotarget 6:379738102015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Li YMSuki DHess KSawaya R: The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?. J Neurosurg 124:9779882016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Liu CTu YSun XJiang JJin XBo X: Wnt/beta-Catenin pathway in human glioma: expression pattern and clinical/prognostic correlations. Clin Exp Med 11:1051122011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Liu XWang LZhao SJi XLuo YLing F: β-Catenin overexpression in malignant glioma and its role in proliferation and apoptosis in glioblastma cells. Med Oncol 28:6086142011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Louis DNOhgaki HWiestler ODCavenee WK: WHO Classification of Tumours of the Central Nervous System Lyon, FranceIARC2007

  • 22

    Marsh JCGoldman SZiel EBregman CDiaz AByrne R: Involvement of the neural stem cell compartment by pediatric and adult gliomas: a retrospective review of 377 cases. J Neurooncol 122:1051102015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Nakano I: Stem cell signature in glioblastoma: therapeutic development for a moving target. J Neurosurg 122:3243302015

  • 24

    Nguyen GDelarue FBurcklé CBouzhir LGiller TSraer JD: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109:141714272002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Ohba KSuzuki TNishiyama HKaneko KHirose TTotsune K: Expression of (pro)renin receptor in breast cancers and its effect on cancer cell proliferation. Biomed Res 35:1171262014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Ohgaki HKleihues P: The definition of primary and secondary glioblastoma. Clin Cancer Res 19:7647722013

  • 27

    Ohgaki HKleihues P: Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100:223522412009

  • 28

    Parsons DWJones SZhang XLin JCLeary RJAngenendt P: An integrated genomic analysis of human glioblastoma multiforme. Science 321:180718122008

  • 29

    Pérez-Sayáns MSomoza-Martín JMBarros-Angueira FRey JMGarcía-García A: V-ATPase inhibitors and implication in cancer treatment. Cancer Treat Rev 35:7077132009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Pu PZhang ZKang CJiang RJia ZWang G: Down-regulation of Wnt2 and beta-catenin by siRNA suppresses malignant glioma cell growth. Cancer Gene Ther 16:3513612009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Pulvirenti TVan Der Heijden MDroms LAHuse JTTabar VHall A: Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas. Cancer Res 71:728072902011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Shibayama YFujimori TNguyen GHirose TTotsune KIchihara A: (Pro)renin receptor is crucial for Wnt/β-catenin-dependent genesis of pancreatic ductal adenocarcinoma. Sci Rep 5:88542015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Singh SKClarke IDTerasaki MBonn VEHawkins CSquire J: Identification of a cancer stem cell in human brain tumors. Cancer Res 63:582158282003

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Singh SKHawkins CClarke IDSquire JABayani JHide T: Identification of human brain tumour initiating cells. Nature 432:3964012004

  • 35

    Stupp RHegi MEMason WPvan den Bent MJTaphoorn MJJanzer RC: 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 10:4594662009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Sun MZOh TIvan MEClark AJSafaee MSayegh ET: Survival impact of time to initiation of chemoradiotherapy after resection of newly diagnosed glioblastoma. J Neurosurg 122:114411502015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Takahashi KYamamoto HHirose THiraishi KShoji IShibasaki A: Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy. Peptides 31:140514082010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Takano SIshikawa ESakamoto NMatsuda MAkutsu HNoguchi M: Immunohistochemistry on IDH 1/2, ATRX, p53 and Ki-67 substitute molecular genetic testing and predict patient prognosis in grade III adult diffuse gliomas. Brain Tumor Pathol 33:1071162016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Takano SKato YYamamoto TKaneko MKIshikawa ETsujimoto Y: Immunohistochemical detection of IDH1 mutation, p53, and internexin as prognostic factors of glial tumors. J Neurooncol 108:3613732012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    van Engeland MNieland LJRamaekers FCSchutte BReutelingsperger CP: Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31:191998

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Watanabe TNobusawa SKleihues POhgaki H: IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:114911532009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Yamamoto HKaneko KOhba KMorimoto RHirose TSatoh F: Increased expression of (pro)renin receptor in aldosterone-producing adenomas. Peptides 49:68732013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Yan HParsons DWJin GMcLendon RRasheed BAYuan W: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:7657732009

  • 44

    Zhang KZhang JHan LPu PKang C: Wnt/beta-catenin signaling in glioma. J Neuroimmune Pharmacol 7:7407492012

  • 45

    Zheng HYing HWiedemeyer RYan HQuayle SNIvanova EV: PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell 17:4975092010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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