Skip to main content
SpringerLink
Log in

PCNA levels in neuroblastoma are increased in tumors with an amplified N-myc gene and in metastatic stage tumors

  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

N-myc oncogene amplification in neuroblastoma has been found to be significantly associated with advanced stage disease and tumor progression. However, there is a lack of data on tumors, regarding the relationship between N-myc gene amplification and proliferation activity. Proliferating cell nuclear antigen (PCNA) is a proliferation-induced 36 kD nuclear protein that is the auxiliary component of DNA polymerase δ. PCNA levels in tissues have been found to correlate with proliferative activity. We have examined PCNA levels in neuroblastomas in relation to N-myc gene amplification and tumor stage. Statistically, significantly higher levels of PCNA were observed in tumors with an amplified N-myc gene relative to tumors with a single gene copy. The highest levels of PCNA were observed in advanced stage tumors with an amplified N-myc gene. Treatment of neuroblastoma cells in culture with retinoic acid, which induces differentiation, resulted in a substantial decrease in PCNA. Our results suggest that PCNA levels may reflect differences in proliferative activity between neuroblastomas, related to stage of the disease and to N-myc gene copy number.[/p ]

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. Bishop JM, 1991, Molecular themes in oncogenesis.Cell,64, 235–248.

    Google Scholar 

  2. Miyachi K, Fritzler MJ and Tan EM, 1978, Autoantibody to a nuclear antigen in proliferation.Journal of Immunology,121, 2228–2234.

    Google Scholar 

  3. Mathews MB, Bernstein RM, Franza BR and Garrels JI, 1984, Identity of the proliferating cell nuclear antigen and cyclin.Nature,309, 374–376.

    Google Scholar 

  4. Asero R, Origgi L, Crespi S, Bertetti E, D'Agostino P and Riboldi P, 1987, Autoantibody to proliferating cell nuclear antigen (PCNA) in SLE: a clinical and serological study.Clinical and Experimental Rheumatology,5, 241–246.

    Google Scholar 

  5. Celis JE, Madsen P, Celis A, Nielsen HV and Gesser B, 1987, Cyclin (PCNA, auxiliary protein of DNA polymerase δ) is a central component of the pathway(s) leading to DNA replication and cell division.FEBS Letters,220, 1–7.

    Google Scholar 

  6. Bravo R, 1986, Synthesis of the nuclear protein cyclin (PCNA) and its relationship with DNA replication.Experimental Cell Research,163, 287–293.

    Google Scholar 

  7. Kurki P, Lotz M, Ogata K and Tan EM, 1987, Proliferating cell nuclear antigen (PCNA)/cyclin in activated human T lymphocytes.Journal of Immunology,138, 4114–4120.

    Google Scholar 

  8. Ogata K, Celis JE and Tan EM, 1987, Proliferating cell nuclear antigen: cyclin.Methods in Enzymology,150, 147–159.

    Google Scholar 

  9. Bravo R and Celis JE, 1980, A search for differential polypeptide synthesis throughout the cell cycle of HeLa cells.Journal of Cell Biology,84, 795–802.

    Google Scholar 

  10. Jaskulski D, DeRiel JK, Mercer WE, Calabretta B and Baserga R, 1988, Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin.Science,240, 1544–1546.

    Google Scholar 

  11. Robbins BA, de la Vega D, Ogata K, Tan EM and Nakamura RM, 1987, Immunohistochemical detection of proliferating cell nuclear antigen in solid human malignancies.Archives of Pathology and Laboratory Medicine 111, 841–845.

    Google Scholar 

  12. Takasaki Y, Robinson WA and Tan EM, 1984, Proliferating cell nuclear antigen in blast crisis cells of patients with chronic myeloid leukemia.Journal of the National Cancer Institute,73, 655–661.

    Google Scholar 

  13. Keim D, Hailat N, Hodge D and Hanash SM, 1990, Proliferating cell nuclear antigen expression in childhood acute leukemia.Blood,76, 985–990.

    Google Scholar 

  14. Brodeur GM, Seeger RC, Schwab M, Varmus HE and Bishop JM, 1984, Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.Science,224, 1121–1124.

    Google Scholar 

  15. Schwab M, Ellison J, Busch M, Rosenau W, Varmus HE and Bishop JM, 1984, Enhanced expression of the human gene N-myc consequent to amplification of DNA may contribute to malignant progression of neuroblastoma.Proceedings of the National Academy of Sciences, USA,81, 4940–4944.

    Google Scholar 

  16. Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY and Hammond D, 1985, Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastoma.New England Journal of Medicine,313, 1111–1116.

    Google Scholar 

  17. Tsuda T, Obara M, Hirano H, Gotoh S, Kubomura S, Higashi K, Kuroiwa A, Nakagawara A, Nagahara N and Shimizu K, 1987, Analysis of N-myc amplification in relation to disease stage and histologic types in human neuroblastomas.Cancer,60, 820–826.

    Google Scholar 

  18. Grady-Leopard EF, Schwab M, Ablin AR and Rosenau W, 1986, Detection of N-myc oncogene expression in human neuroblastoma byin situ hybridization blot analysis: relationships to clinical outcome.Cancer Research,46, 3196–3199.

    Google Scholar 

  19. Koop CE and Johnson DG, 1971, Neuroblastoma: an assessment of therapy in reference to staging.Journal of Pediatric Surgery,6, 595–600.

    Google Scholar 

  20. Evans AE, Albo V, D'Angio GJ, Finklestein JZ, Leiken S, Santalli T, Weiner J and Hammond GD, 1976, Factors influencing survival of children with non-metastatic neuroblastoma.Cancer,38, 661–666.

    Google Scholar 

  21. Breslow N and McCann B, 1971, Statistical estimation of prognosis for children with neuroblastoma.Cancer Research,31, 2098–2103.

    Google Scholar 

  22. Phillips WS, Stafford PW, Duvol-Arnold B and Ghosh BC, 1991, Neuroblastoma and the clinical significance of N-myc oncogene amplification.Surgical Gynecology and Obstetrics,172, 73–80.

    Google Scholar 

  23. Hailat N, Keim DR, Melhem RF, Zhu X-X, Eckerskorn C, Brodeur GM, Reynolds CP, Seeger RC, Lottspeich F, Strahler JR and Hanash SM, 1991, High levels of P19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification.Journal of Clinical Investigations,88, 341–345.

    Google Scholar 

  24. Hailat N, Strahler J, Melhem R, Zhu X-X, Brodeur G, Seeger RC, Reynolds CP and Hanash SM, 1990, N-myc gene amplification in neuroblastoma is associated with altered phosphorylation of a proliferation related polypeptide (Opl8).Oncogene,5, 1615 -1618.

    Google Scholar 

  25. Sidell N, Altmann A, Haussler MR and Seeger RC, 1983, Effects of retinoic acid (RA) on the growth and phenotypic expression of several human neuro blastoma cell lines.Experimental Cell Research,148, 21–30.

    Google Scholar 

  26. Thiele CJ, Reynolds CP and Israel MA, 1985, Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma.Nature,313, 404–406.

    Google Scholar 

  27. Strahler JR, Kuick R and Hanash SM. Two-dimensional polyacrylamide gel electrophoresis of proteins. In: Creighton T, ed.Protein Structure: a practical approach, pp. 65–92. Oxford: IRL Press, 1989.

    Google Scholar 

  28. Merril CR, Goldman D, Sedman SA and Ebert MA, 1981, Ultrasensitive stain for proteins in polyacrylamide gels show regional variation in cerebrospinal fluid.Science,211, 1437–1438.

    Google Scholar 

  29. Kuick R, Hanash SM, Chu EHY and Strahler JR, 1987, A comparison of some adjustment techniques for use with quantitative spot data.Electrophoresis,8, 199–204.

    Google Scholar 

  30. Ogata K, Kurki P, Celis JE, Nakamura RM and Tan EM, 1987, Monoclonal antibodies to a nuclear protein (PCNA/cyclin) associated with DNA replication.Experimental Cell Research,168, 475–486.

    Google Scholar 

  31. Haskell BF, Stach RW, Werrbach-Perez K and Perez-Polo JR, 1987, Effect of retinoic acid on nerve growth factor receptors.Cell Tissue Research,247, 67–73.

    Google Scholar 

  32. Willnow V, 1979, The kinetics of cell proliferation in neuroblastoma.Archiv fur Geschwulstforschung,49, 211–219.

    Google Scholar 

  33. Wagner HP and Kaser H, 1970, Cell proliferation in neuroblastoma.European Journal of Cancer,6, 369–372.

    Google Scholar 

  34. Tay DLM, Bhathal PS and Fox RM, 1990, Quantitation of G0 and G1 phase cells in primary carcinomas.Journal of Clinical Investigations,87, 519–527.

    Google Scholar 

  35. Cohn SL, Rademaker AW, Salwen HR, Franklin WA, Gonzales-Crussi F, Rosen ST and Bauer KD, 1990, Analysis of DNA ploidy and proliferative activity in relation to histology and N-myc amplification in neuroblastoma.American Journal of Pathology,136, 1043–1052.

    Google Scholar 

  36. Cohn SL, Salwen H, Quasney MW, Ikegaki N, Cowan JM, Herst CV, Kennett RH, Rosen ST, DiGuisseppe JA and Brodeur GM, 1990, Prolonged N-myc protein half life in a neuroblastoma cell line lacking N-myc amplification.Oncogene,5, 1821–1827.

    Google Scholar 

  37. Hammerling U, Bjelfman C and Pahlman S, 1987, Different regulation of N- and c-myc expression during phorbol ester-induced maturation of human SH-SYSY neuroblastoma cells.Oncogene,2, 73–77.

    Google Scholar 

Download references

Author information

Author notes

  1. Nabil Hailat

    Present address: Faculty of Veterinary Medicine, Jordan University of Science and Technology, Irbid, Israel

Authors and Affiliations

  1. Department of Pediatric Hematology, University of Michigan Medical School, R4451 Kresge I, Box 0510, 48109-0510, Ann Arbor, MI

    David R. Keim, Nabil Hailat, Rork Kuick & Samir M. Hanash

  2. Childrens Hospital of Los Angeles, Department of Pediatrics, Division of Pediatric Hematology/Oncology and Children's Cancer Study Group, University of Southern California School of Medicine, 90027, Los Angeles, CA

    C. Patrick Reynolds & Robert C. Seeger

  3. Department of Pediatrics and Pediatric Oncology Group, Washington University School of Medicine, 63310, St Louis, MO, USA

    Garrett M. Brodeur

Authors
  1. David R. Keim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nabil Hailat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rork Kuick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Patrick Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Garrett M. Brodeur
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert C. Seeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Samir M. Hanash
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keim, D.R., Hailat, N., Kuick, R. et al. PCNA levels in neuroblastoma are increased in tumors with an amplified N-myc gene and in metastatic stage tumors. Clin Exp Metast 11, 83–90 (1993). https://doi.org/10.1007/BF00880069

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00880069

Keywords

Search

Navigation