Skip to main content

Advertisement

SpringerLink
Log in

Expression of the constitutively activated RelA/NF-κB in human astrocytic tumors and the in vitro implication in the regulation of urokinase-type plasminogen activator, migration, and invasion

  • ORIGINAL ARTICLE
  • Published:
Brain Tumor Pathology Aims and scope Submit manuscript

Abstract

Although malignant gliomas are highly invasive tumors, a characteristic that contributes to the commonly observed therapeutic failures and local disease recurrences, the molecular events that regulate invasion in these tumors remain poorly understood. Because the transcription factor RelA/NF-κB has been shown to regulate invasion during several cellular processes, we have examined immunohistochemically expression of the constitutively activated RelA/NF-κB in tissues obtained from 49 astrocytic tumors [8 diffuse astrocytomas, 9 anaplastic astrocytomas (AAs) and 32 glioblastomas (GBMs)]. In addition, we examined the in vitro effects of antisense oligonucleotides and curcumin on the expression and activation of RelA/NF-κB, urokinase-type plasminogen activator (u-PA) expression, migration, and invasion in the T98G glioma cell line. Expression of the constitutively activated RelA/NF-κB was observed in 2 (25%) of 8 cases of diffuse astrocytomas, 5 (55.6%) of 9 cases of AAs, and 30 (93.8%) of 32 cases of GBMs. This expression was significantly correlated with the malignant potential in astrocytic tumors (P < 0.001). Moreover, antisense oligonucleotides and curcumin inhibited phorbol-12-myristate-13-acetate (PMA)-induced RelA/NF-κB expression or activation (or both), down-regulated u-PA expression, and reduced the migration and invasive potentials of T98G glioma cells. Thus, the expression of constitutively activated RelA/NF-κB is associated with malignancy potential in astrocytic tumors and may play a critical role in the regulation of u-PA expression and invasiveness in gliomas. RelA/NF-κB may therefore be an intriguing candidate for studies aimed at understanding and prevention of the invasiveness of gliomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. SA Assisi C Miyamoto (1998) ArticleTitlePrinciples of treatment of malignant gliomas in adults: an overview J Neurovirol 4 204–216

    Google Scholar 

  2. PC Burger ER Heinz T Shibata et al. (1988) ArticleTitleTopographic anatomy and CT correlations in the untreated glioblastoma multiforme J Neurosurg 68 698–704 Occurrence Handle2833587 Occurrence Handle1:STN:280:BieC1cjnvFM%3D

    PubMed  CAS  Google Scholar 

  3. FH Hochberg A Pruitt (1980) ArticleTitleAssumptions in the radiotherapy of glioblastoma Neurology 30 907–911 Occurrence Handle6252514 Occurrence Handle1:STN:280:Bi6D3s7isVA%3D

    PubMed  CAS  Google Scholar 

  4. MJ Duffy (1996) ArticleTitleProteases as prognostic markers in cancer Clin Cancer Res 2 613–618 Occurrence Handle9816210 Occurrence Handle1:CAS:528:DyaK28Xis1Wltb4%3D

    PubMed  CAS  Google Scholar 

  5. D Boyd (1989) ArticleTitleExamination of the effects of epidermal growth factor on the production of urokinase and the expression of the plasminogen activator receptor in a human colon cancer cell line Cancer Res 49 2427–2432 Occurrence Handle2539903 Occurrence Handle1:CAS:528:DyaL1MXit1Kisrw%3D

    PubMed  CAS  Google Scholar 

  6. F Janicke M Schmitt K Ulm et al. (1989) ArticleTitleUrokinase-type plasminogen activator antigen and early relapse in breast cancer Lancet 2 1049 Occurrence Handle2572788 Occurrence Handle1:STN:280:By%2BD2c3nsFc%3D

    PubMed  CAS  Google Scholar 

  7. W Kuhn L Pache B Schmalfeldt et al. (1994) ArticleTitleUrokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy Gynecol Oncol 55 401–409 Occurrence Handle7835780 Occurrence Handle10.1006/gyno.1994.1313 Occurrence Handle1:STN:280:ByqC3sjkslQ%3D

    Article  PubMed  CAS  Google Scholar 

  8. K Dano PA Andreasen J Grondahl-Hansen et al. (1985) ArticleTitlePlasminogen activators, tissue degradation, and cancer Adv Cancer Res 44 139–266 Occurrence Handle2930999 Occurrence Handle1:STN:280:BiqA3czkslM%3D

    PubMed  CAS  Google Scholar 

  9. WG Stetler-Stevenson S Aznavoorian LA Liotta (1993) ArticleTitleTumor cell interactions with the extracellular matrix during invasion and metastasis Annu Rev Cell Biol 9 541–573 Occurrence Handle8280471 Occurrence Handle10.1146/annurev.cb.09.110193.002545 Occurrence Handle1:CAS:528:DyaK2cXltFamsw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  10. M Yamamoto R Sawaya S Mohanam et al. (1994) ArticleTitleExpression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo Cancer Res 54 3656–3661 Occurrence Handle8033079 Occurrence Handle1:CAS:528:DyaK2cXltVGmtrw%3D

    PubMed  CAS  Google Scholar 

  11. A Reith GJ Rucklidge (1992) ArticleTitleInvasion of brain tissue by primary glioma: evidence for the involvement of urokinase-type plasminogen activator as an activator of type IV collagenase Biochem Biophys Res Commun 186 348–354 Occurrence Handle1321608 Occurrence Handle10.1016/S0006-291X(05)80814-9 Occurrence Handle1:STN:280:By2A3sjmtF0%3D

    Article  PubMed  CAS  Google Scholar 

  12. DH Kinder MS Berger BA Mueller (1993) ArticleTitleUrokinase plasminogen activator is elevated in human astrocytic gliomas relative to normal adjacent brain Oncol Res 5 409–414 Occurrence Handle8054701 Occurrence Handle1:CAS:528:DyaK2cXltVGnu7s%3D

    PubMed  CAS  Google Scholar 

  13. BJ Landau HC Kwaan EN Verrusio et al. (1994) ArticleTitleElevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 in malignant human brain tumors Cancer Res 54 1105–1108 Occurrence Handle8313368 Occurrence Handle1:STN:280:ByuC2cjjvFc%3D

    PubMed  CAS  Google Scholar 

  14. S Mohanam CL Gladson CN Rao (1999) ArticleTitleBiological significance of the expression of urokinase-type plasminogen activator receptors (uPARs) in brain tumors Front Biosci 4 D178–D187 Occurrence Handle9989951 Occurrence Handle1:CAS:528:DyaK1MXitFKjtrk%3D

    PubMed  CAS  Google Scholar 

  15. S Mohanam Y Go R Sawaya et al. (1999) ArticleTitleElevated levels of urokinase-type plasminogen activator and its receptor during tumor growth in vivo Int J Oncol 14 169–174 Occurrence Handle9863025 Occurrence Handle1:CAS:528:DyaK1MXktlKnug%3D%3D

    PubMed  CAS  Google Scholar 

  16. X Zhang Z Fei X Bu et al. (2000) ArticleTitleExpression and significance of urokinase type plasminogen activator gene in human brain gliomas J Surg Oncol 74 90–94 Occurrence Handle10914816 Occurrence Handle10.1002/1096-9098(200006)74:2<90::AID-JSO2>3.0.CO;2-7 Occurrence Handle1:CAS:528:DC%2BD3cXltFSlu70%3D

    Article  PubMed  CAS  Google Scholar 

  17. H Engelhard C Narang R Homer (1996) ArticleTitleUrokinase antisense oligodeoxynucleotides as a novel therapeutic agent for malignant glioma: in vitro and in vivo studies of uptake, effects and toxicity Biochem Biophys Res Commun 227 400–405 Occurrence Handle8878527 Occurrence Handle10.1006/bbrc.1996.1519 Occurrence Handle1:CAS:528:DyaK28Xmt1Kgtrw%3D

    Article  PubMed  CAS  Google Scholar 

  18. G Kitange S Shibata Y Tokunaga et al. (1999) ArticleTitleEts-1 transcription factor-mediated urokinase-type plasminogen activator expression and invasion in glioma cells stimulated by serum and basic fibroblast growth factors Lab Invest 79 407–416 Occurrence Handle10211993 Occurrence Handle1:CAS:528:DyaK1MXivVGku74%3D

    PubMed  CAS  Google Scholar 

  19. PA Baeuerle D Baltimore (1996) ArticleTitleNF-kappa B: ten years after Cell 87 13–20 Occurrence Handle8858144 Occurrence Handle10.1016/S0092-8674(00)81318-5 Occurrence Handle1:CAS:528:DyaK28XmtFeit7g%3D

    Article  PubMed  CAS  Google Scholar 

  20. SA Schwartz A Hernandez B Mark Evers (1999) ArticleTitleThe role of NF-kappaB/IkappaB proteins in cancer: implications for novel treatment strategies Surg Oncol 8 143–153 Occurrence Handle11113665 Occurrence Handle10.1016/S0960-7404(00)00012-8 Occurrence Handle1:STN:280:DC%2BD3M%2FosFGkug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  21. SY Foo GP Nolan (1999) ArticleTitleNF-kappaB to the rescue: RELs, apoptosis and cellular transformation Trends Genet 15 229–235 Occurrence Handle10354583 Occurrence Handle1:CAS:528:DyaK1MXjvVGqtb4%3D

    PubMed  CAS  Google Scholar 

  22. S Ghosh MJ May EB Kopp (1998) ArticleTitleNF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses Annu Rev Immunol 16 225–260 Occurrence Handle9597130 Occurrence Handle10.1146/annurev.immunol.16.1.225 Occurrence Handle1:CAS:528:DyaK1cXislygtL0%3D

    Article  PubMed  CAS  Google Scholar 

  23. PA Baeuerle D Baltimore (1988) ArticleTitleI kappa B: a specific inhibitor of the NF-kappa B transcription factor Science 242 540–546 Occurrence Handle3140380 Occurrence Handle1:CAS:528:DyaL1cXmt1yiuro%3D

    PubMed  CAS  Google Scholar 

  24. SK Hansen C Nerlov U Zabel et al. (1992) ArticleTitleA novel complex between the p65 subunit of NF-kappa B and c-Rel binds to a DNA element involved in the phorbol ester induction of the human urokinase gene EMBO J 11 205–213 Occurrence Handle1740106 Occurrence Handle1:CAS:528:DyaK38Xhs1ynurk%3D

    PubMed  CAS  Google Scholar 

  25. W Wang JL Abbruzzese DB Evans et al. (1999) ArticleTitleOverexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA Oncogene 18 4554–4563 Occurrence Handle10467400 Occurrence Handle1:CAS:528:DyaK1MXlslCrtbc%3D

    PubMed  CAS  Google Scholar 

  26. W Wang JL Abbruzzese DB Evans et al. (1999) ArticleTitleThe nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells Clin Cancer Res 5 119–127 Occurrence Handle9918209 Occurrence Handle1:CAS:528:DyaK1MXhtVShtLY%3D

    PubMed  CAS  Google Scholar 

  27. B Rayet C Gelinas (1999) ArticleTitleAberrant rel/nfkb genes and activity in human cancer Oncogene 18 6938–6947 Occurrence Handle10602468 Occurrence Handle10.1038/sj.onc.1203221 Occurrence Handle1:CAS:528:DyaK1MXotVyhtb4%3D

    Article  PubMed  CAS  Google Scholar 

  28. H Nakshatri P Bhat-Nakshatri DA Martin et al. (1997) ArticleTitleConstitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth Mol Cell Biol 17 3629–3639 Occurrence Handle9199297 Occurrence Handle1:CAS:528:DyaK2sXktFOhtLY%3D

    PubMed  CAS  Google Scholar 

  29. S Huang A DeGuzman CD Bucana et al. (2000) ArticleTitleNuclear factor-kappa B activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice Clin Cancer Res 6 2573–2581 Occurrence Handle10873114 Occurrence Handle1:CAS:528:DC%2BD3cXksVGhtrk%3D

    PubMed  CAS  Google Scholar 

  30. L Guerrini L Casalino A Corti et al. (1996) ArticleTitleNF-kappa B-mediated regulation of urokinase gene expression by PMA and TNF-alpha in human A549 cells FEBS Lett 393 69–73 Occurrence Handle8804426 Occurrence Handle10.1016/0014-5793(96)00854-X Occurrence Handle1:CAS:528:DyaK28XlsFWkt74%3D

    Article  PubMed  CAS  Google Scholar 

  31. N Mori M Fujii S Ikeda et al. (1999) ArticleTitleConstitutive activation of NF-kappaB in primary adult T-cell leukemia cells Blood 93 2360–2368 Occurrence Handle10090947 Occurrence Handle1:CAS:528:DyaK1MXit1Khtbc%3D

    PubMed  CAS  Google Scholar 

  32. U Reuning O Wilhelm T Nishiguchi et al. (1995) ArticleTitleInhibition of NF-kappa B-Rel A expression by antisense oligodeoxynucleotides suppresses synthesis of urokinase-type plasminogen activator (uPA) but not its inhibitor PAI-1 Nucleic Acids Res 23 3887–3893 Occurrence Handle7479032 Occurrence Handle1:CAS:528:DyaK2MXptFWlsrs%3D

    PubMed  CAS  Google Scholar 

  33. CK Ritchie A Giordano K Khalili (2000) ArticleTitleIntegrin involvement in glioblastoma multiforme: possible regulation by NF-kappaB J Cell Physiol 184 214–221 Occurrence Handle10867646 Occurrence Handle10.1002/1097-4652(200008)184:2<214::AID-JCP9>3.0.CO;2-Z Occurrence Handle1:CAS:528:DC%2BD3cXks1yksb8%3D

    Article  PubMed  CAS  Google Scholar 

  34. P Chomczynski N Sacchi (1987) ArticleTitleSingle-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction Anal Biochem 162 156–159 Occurrence Handle2440339 Occurrence Handle10.1016/0003-2697(87)90021-2 Occurrence Handle1:CAS:528:DyaL2sXitFSns7Y%3D

    Article  PubMed  CAS  Google Scholar 

  35. YJ Surh SS Han YS Keum et al. (2000) ArticleTitleInhibitory effects of curcumin and capsaicin on phorbol ester-induced activation of eukaryotic transcription factors, NF-kappaB and AP-1 Biofactors 12 107–112 Occurrence Handle11216470 Occurrence Handle1:CAS:528:DC%2BD3MXhsFegur8%3D

    PubMed  CAS  Google Scholar 

  36. C Jobin CA Bradham MP Russo et al. (1999) ArticleTitleCurcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity J Immunol 163 3474–3483 Occurrence Handle10477620 Occurrence Handle1:CAS:528:DyaK1MXlvV2lt7o%3D

    PubMed  CAS  Google Scholar 

  37. S Hayashi M Yamamoto Y Ueno et al. (2001) ArticleTitleExpression of nuclear factor-kappa B, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas Neurol Med Chir (Tokyo) 41 IssueID4 187–195 Occurrence Handle10.2176/nmc.41.187 Occurrence Handle1:STN:280:DC%2BD3M3psVymtg%3D%3D

    Article  CAS  Google Scholar 

  38. M Nakada J Yamashita Y Okada et al. (1999) ArticleTitleEts-1 positively regulates expression of urokinase-type plasminogen activator (uPA) and invasiveness of astrocytic tumors J Neuropathol Exp Neurol 58 329–334 Occurrence Handle10218628 Occurrence Handle1:CAS:528:DyaK1MXivVygsbk%3D

    PubMed  CAS  Google Scholar 

  39. U Siebenlist G Franzoso K Brown (1994) ArticleTitleStructure, regulation and function of NF-κB Annu Rev Cell Biol 10 405–455 Occurrence Handle7888182 Occurrence Handle10.1146/annurev.cb.10.110194.002201 Occurrence Handle1:CAS:528:DyaK2MXitlSnsb8%3D

    Article  PubMed  CAS  Google Scholar 

  40. VB Andela EM Schwarz JE Puzas et al. (2000) ArticleTitleTumor metastasis and the reciprocal regulation of prometastatic and anti metastatic factors by nuclear factor kappaB Cancer Res 60 6557–6562 Occurrence Handle11118032 Occurrence Handle1:CAS:528:DC%2BD3cXosl2isLo%3D

    PubMed  CAS  Google Scholar 

  41. SA Raithatha H Muzik NB Rewcastle et al. (2000) ArticleTitleLocalization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas Neurooncology 2 145–150 Occurrence Handle1:STN:280:DC%2BD3M3jsF2htQ%3D%3D

    CAS  Google Scholar 

  42. Z Kachra E Beaulieu L Delbecchi et al. (1999) ArticleTitleExpression of matrix metalloproteinases and their inhibitors in human brain tumors Clin Exp Metastasis 17 555–566 Occurrence Handle10845554 Occurrence Handle10.1023/A:1006760632766 Occurrence Handle1:CAS:528:DC%2BD3cXksl2mu7k%3D

    Article  PubMed  CAS  Google Scholar 

  43. T Watabe K Yoshida M Shindoh et al. (1998) ArticleTitleThe Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor Int J Cancer 77 128–137 Occurrence Handle9639404 Occurrence Handle10.1002/(SICI)1097-0215(19980703)77:1<128::AID-IJC20>3.0.CO;2-9 Occurrence Handle1:CAS:528:DyaK1cXkt1WhtL8%3D

    Article  PubMed  CAS  Google Scholar 

  44. A Nishikawa M Iwasaki N Akutagawa et al. (2000) ArticleTitleExpression of various matrix proteases and Ets family transcriptional factors in ovarian cancer cell lines: correlation to invasive potential Gynecol Oncol 79 256–263 Occurrence Handle11063654 Occurrence Handle10.1006/gyno.2000.5944 Occurrence Handle1:CAS:528:DC%2BD3cXnslGjtL8%3D

    Article  PubMed  CAS  Google Scholar 

  45. JS Gill X Zhu MJ Moore et al. (2002) ArticleTitleEffect of NFκB decoy oligonucleotides released from biodegradable polymer microparticles on a glioblastoma cell line Biomaterials 23 2773–2781 Occurrence Handle12059028 Occurrence Handle10.1016/S0142-9612(02)00013-3 Occurrence Handle1:CAS:528:DC%2BD38XjsVSqsbc%3D

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Nagasaki University School of Medicine, 1-7-1 Sakamoto-machi, Nagasaki, 852-8501, Japan

    Keishi Tsunoda, Gaspar Kitange, Takeo Anda, Hamisi Kimaro Shabani, Makio Kaminogo, Shobu Shibata & Izumi Nagata

Authors
  1. Keishi Tsunoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gaspar Kitange
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takeo Anda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hamisi Kimaro Shabani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Makio Kaminogo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shobu Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Izumi Nagata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keishi Tsunoda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsunoda, K., Kitange, G., Anda, T. et al. Expression of the constitutively activated RelA/NF-κB in human astrocytic tumors and the in vitro implication in the regulation of urokinase-type plasminogen activator, migration, and invasion. Brain Tumor Pathol 22, 79–87 (2005). https://doi.org/10.1007/s10014-005-0186-1

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10014-005-0186-1

Key words

Search

Navigation