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Immunocytochemical detection of 14-3-3 in primary nervous system tumors

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Summary

14-3-3 proteins have attracted much recent interest in the etiopathogenesis of human cancers owing to their involvement in the prevention of apoptosis. However, the expression of 14-3-3 in primary nervous system tumors has not been previously characterized. In this paper, Immunohistochemistry using a specific anti-14-3-3 antibody was performed on formalin-fixed, paraffin embedded archival tissue from 124 primary human nervous system tumors and 10 normal brain tissues. In the normal control brains, 14-3-3 immunoreactivity was localized mainly in the neuronal somata and processes, and some glial cells showed only weak immunoreactivity. However, 14-3-3 immunoreactivity was seen in the majority of astrocytomas [grade I (9/11), II (16/21), III (13/17), IV (17/21)]. There was no difference between the positive expression rates of 14-3-3 in different grades of astrocytomas (= 0.968). But the intensity and degree of 14-3-3 immunoreactivity in diffuse astrocytomas, anaplastic astrocytoma, and glioblastoma multiformes showed trends with tumor grade, with glioblastomas having the highest positivity (= 0.048). The 14-3-3 immunoreactivity was also seen in the majority of other gliomas [oligodendroglioma (2/3), anaplastic oligodendroglioma (4/4), ependymoma (1/2), anaplastic ependymoma (2/2), choroid plexus papilloma (3/3), pineocytoma (2/2), medulloblastoma (5/8)]. All meningiomas [syncytical (3), fibrous/fibroblastic (4), angiomatous (4), transitional/mixed (3)] were intensely and diffusely positive. All schwannomas (4), neurofibromas (2), pituitary adenomas (6) and craniopharyngiomas(4) also showed intense positive staining. These results showed that 14-3-3 is expressed in the majority of the primary human nervous system tumors. The up-regulated expression of 14-3-3 may be a common mechanism for evading apoptosis in most primary human nervous system tumors, and targeting 14-3-3 may be a novel promising strategy for the treatment of these tumors, especially for malignant tumors.

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References

  1. Aitken A, Collinge DB, van Heusden BP, Isobe T, Roseboom PH, Rosenfeld G, Soll J, 14-3-3 proteins: a highly conserved, widespread family of eukaryotic proteins Trend Biochem Sci 17:498–501, 1992

    Article  PubMed  CAS  Google Scholar 

  2. Ferl RJ, Manak MS, Reyes MF, The 14-3-3s Genome Biol 3:3010.1–3010.7, 2002

    Article  Google Scholar 

  3. Moore BW, Perez VJ, 1967 Specific acid proteins in the nervous system. In: Carlson FD, ed Physiological and Biochemical Aspects of Nervous Integration. Prentice Hall/Woods Hole, Woods Hole, pp 343–359

    Google Scholar 

  4. van Hemert MJ, Steensma HY, van Heusden GP, 14-3-3 proteins: key regulators of cell division, signalling and apoptosis Bioessays 23:936–946, 2001

    Article  PubMed  Google Scholar 

  5. Boston PF, Jackson P, Kynoch PAM, Thompson RJ, Purification, properties, and immunohistochemical localisation of human brain 14-3-3 protein J Neurochem 38:1466–1474, 1982

    Article  PubMed  CAS  Google Scholar 

  6. Baxter HC, Fraser JR, Liu WG, Forster JL, Clokie S, Steinacker P, Otto M, Bahn E, Wiltfang J, Aitken A, Specific 14-3-3 isoform detection and immunolocalization in prion diseases Biochem Soc Trans 30:387–391, 2002

    Article  PubMed  CAS  Google Scholar 

  7. Fu H, Subramanian RR, Masters SC, 14-3-3 proteins: structure, function, and regulation Annu Rev Pharmacol Toxicol 40:617–647, 2000

    Article  PubMed  CAS  Google Scholar 

  8. Martin H, Patel Y, Jones D, Howell S, Robinson K, Aitken A, Antibodies against the major brain isoforms of 14-3-3 protein. An antibody specific for the N-acetylated amino-terminus of a protein FEBS Lett 331:296–303, 1993

    Article  PubMed  CAS  Google Scholar 

  9. Pozuelo Rubio M, Geraghty KM, Wong BH, Wood NT, Campbell DG, Morrice N, Mackintosh C, 14-3-3-Affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation, and trafficking Biochem J 379:395–408, 2004

    Article  PubMed  Google Scholar 

  10. Hermeking H, The 14-3-3 cancer connection Nat Rev Cancer 3:931–43, 2003

    Article  PubMed  CAS  Google Scholar 

  11. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ, Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL Cell 87:619–628, 1996

    Article  PubMed  CAS  Google Scholar 

  12. Xing H, Zhang S, Weinheimer C, Kovacs A, Muslin AJ, 14-3-3 proteins block apoptosis and differentially regulate MAPK cascades EMBO J 19:349–358, 2000

    Article  PubMed  CAS  Google Scholar 

  13. Subramanian RR, Masters SC, Zhang H, Fu H, Functional conservation of 14-3-3 isoforms in inhibiting Bad-induced apoptosis Experimental Cell Research 271:142–151, 2001

    Article  PubMed  CAS  Google Scholar 

  14. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME, Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor Cell 96:857–868, 1999

    Article  PubMed  CAS  Google Scholar 

  15. Basu S, Totty NF, Irwin MS, Sudol M, Downward J, Akt phophorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis Mol Cell 11:11–23, 2003

    Article  PubMed  CAS  Google Scholar 

  16. Zhang L, Chen J, Fu H, Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins Proc Natl Acad Sci USA 96:8511–8515, 1999

    Article  PubMed  CAS  Google Scholar 

  17. Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H, Tsujimoto Y, 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax J Biol Chem 278:2058–2065, 2003

    Article  PubMed  CAS  Google Scholar 

  18. Craparo A, Freund R, Gustafson TA, 14-3-3 (epsilon) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner J Biol Chem 272:11663–11669, 1997

    Article  PubMed  CAS  Google Scholar 

  19. Bonnefoy-Berard N, Liu YC, von Willebrand M, Sung A, Elly C, Mustelin T, Yoshida H, Ishizaka K, Altman A, Inhibition of phosphatidylinositol 3-kinase activity by association with 14-3-3 proteins in T cells Proc Natl Acad Sci U S A 92:10142–10146, 1995

    Article  PubMed  CAS  Google Scholar 

  20. Zhang P., Chan SL, Fu W, Mendoza M, Mattson MP, TERT suppresses apoptotis at a premitochondrial step by a mechanism requiring reverse transcriptase activity and 14-3-3 protein binding ability FASEB J 17:767–769, 2003

    PubMed  CAS  Google Scholar 

  21. Beyaert R, Heyninck K, Van Huffel S, A20 and A20-binding proteins as cellular inhibitors of nuclear factor-κB-dependent gene expression and apoptosis Biochem. Pharmacol. 60:1143–1151, 2000

    Article  PubMed  CAS  Google Scholar 

  22. Kleihues P, Cavenee WK, Pathology and genetics of tumours of the nervous system. LARC Press, Lyon, 2000, pp 6–7

    Google Scholar 

  23. Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H, Budka H, 14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains J Neuropathol Exp Neurol 61:245–253, 2002

    PubMed  CAS  Google Scholar 

  24. Kawamoto Y, Akiguchi I, Nakamura S, Budka H, Accumulation of 14-3-3 proteins in glial cytoplasmic inclusions in multiple system atrophy Ann Neurol 52:722–731, 2002

    Article  PubMed  CAS  Google Scholar 

  25. Remmele W, Hildebrand U, Hienz HA, Klein PJ, Vierbuchen M, Behnken LJ, Heicke B, Scheidt E, Comparative histological, histochemical, immunhistochemical and biochemical studies on estrogen receptors, lectin receptors, and Barr bodies in human breast cancer Virchows Arch 409:127–147, 1986

    Article  CAS  Google Scholar 

  26. Boston PF, Jackson P, Thompson RJ, Human 14-3-3 protein: radioimmunoassay, tissue distribution, and cerebrospinal fluid levels in patients with neurological disorders J Neurochem 38:1475–1482, 1982

    Article  PubMed  CAS  Google Scholar 

  27. Kawamoto Y, Akiguchi I, Kovacs GG, Flicker H, Budka H, Increased 14-3-3 immunoreactivity in glial elements in patients with multiple sclerosis Acta Neuropathol (Berl) 107:137–143, 2004

    Article  CAS  Google Scholar 

  28. Rudin CM, Thompson CB, Apoptosis and disease: regulation and clinical relevance of programmed cell death Annu Rev Med 48:267–281, 1997

    Article  PubMed  CAS  Google Scholar 

  29. Newton HB, Molecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors. Part 4:p53 signaling pathway Expert Rev Anticancer Ther 5:177–191, 2005

    Article  PubMed  CAS  Google Scholar 

  30. Johnson MD, Okedli E, Woodard A, Toms SA, Allen GS, Evidence for phosphatidylinositol 3-kinase-Akt-p7S6 K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells J Neurosurg 97:668–675, 2002

    Article  PubMed  CAS  Google Scholar 

  31. Mawrin C, Kirches E, Dietzmann K, Roessner A, Boltze C, Expression pattern of apoptotic markers in vestibular schwannomas Pathol Res Pract 198:813–819. 2002

    Article  PubMed  CAS  Google Scholar 

  32. Kulig E, Jin L, Qian X, Horvath E, Kovacs K, Stefaneanu L, Scheithauer BW, Lloyd RV, Apoptosis in nontumorous and neoplastic human pituitaries: expression of the Bcl-2 family of proteins Am J Pathol 154:767–774, 1999

    PubMed  CAS  Google Scholar 

  33. Nakasu S, Matsumura K, Nioka H, Handa J, Lectin binding and bcl-2 protein expression in craniopharyngiomas Neurol Med Chir (Tokyo) 34:429–435, 1994

    Article  CAS  Google Scholar 

  34. Masters SC, Fu H, Survival-promoting functions of 14-3-3 proteins Biochem Soc Trans 30:360–365, 2002

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Dr. Wei Yan and Dr. Fucheng Ma (Department of Pathology, Xijing Hospital, Fourth Military Medical University) for confirming the histopathological diagnosis of all the samples used in this research and helping to perform microscopic analysis for 14-3-3 immunoreactivity. We thank Dr. Fubo Xue’s help in statistical analysis. And we also thank Ms. Lei Song and Ms. Xiling Wang for material preparing for this research.

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Correspondence to Xiang Zhang.

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Cao, WD., Zhang, X., Zhang, JN. et al. Immunocytochemical detection of 14-3-3 in primary nervous system tumors. J Neurooncol 77, 125–130 (2006). https://doi.org/10.1007/s11060-005-9027-7

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  • DOI: https://doi.org/10.1007/s11060-005-9027-7

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