Advertisement

International Journal of Hematology

, Volume 80, Issue 1, pp 52–58 | Cite as

Clinical Relevance of Survivin as a Biomarker in Neoplasms, Especially in Adult T-Cell Leukemias and Acute Leukemias

  • Kazuyuki Sugahara
  • Akiko Uemura
  • Hitomi Harasawa
  • Hiroshi Nagai
  • Yoichi Hirakata
  • Masao Tomonaga
  • Kenn Murata
  • Hiroshi Sohda
  • Toru Nakagoe
  • Sin-ichi Shibasaki
  • Yasuaki Yamada
  • Shimeru Kamihira
Article

Abstract

Survivin has been identified as one of the top 4 transcripts among 3.5 million human transcriptomes uniformly upregulated in cancer tissues but not in normal tissues. Therefore, we quantitatively determined the messenger RNA (mRNA) expression profile for survivin by a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) technique in 113 patients with leukemias, such as adult T-cell leukemia (ATL), acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia in crisis, and chronic lymphocytic leukemia (CLL), and in 25 cell lines, including 7 ATL cell lines and 15 solid-tumor cell lines. Furthermore, we examined whether the plasma level of survivin protein as measured by enzyme-linked immunosorbent assay (ELISA) substituted for mRNA expression by PCR quantification. Gene expression was quantitatively confirmed to be up-regulated in approximately 90% of ATL and acute leukemia cases and in all of the cell lines tested, whereas it was down-regulated in almost all cases of CLL. Furthermore, with respect to the interpretation of the gene expression findings, attention was paid to standardization with a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in the real-time PCR quantification, because the variability in GAPDH expression among the different cell types was significant. GAPDH expression was relatively low in ATL cells and high in ALL and AML cells. The rates of increase in the levels of survivin protein in the plasma of ATL patients and in the supernatants from in vitro cultures of solid-tumor cell lines were low compared with rates of increase of the mRNA and protein level in the cells, suggesting that the protein levels in plasma do not always reflect survivin expression in tumor cells. Our findings indicate the potential clinical relevance of survivin quantified by real-time PCR but not for the protein level in plasma as determined by ELISA, especially in cases of ATL and acute leukemias.

Key words

Survivin Biomarker Real-time PCR ATL HTLV-1 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer. 2003;3:46–54.CrossRefGoogle Scholar
  2. 2.
    Temme A, Rieger M, Reber F, et al. Localization, dynamics, and function of survivin revealed by expression of functional survivin- DsRed fusion proteins in the living cell. Mol Biol Cell. 2003;14: 78–92.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997;3: 917–921.CrossRefGoogle Scholar
  4. 4.
    Carter BZ, Milella M, Altieri DC, Andreeff M. Cytokine-regulated expression of survivin in myeloid leukemia. Blood. 2001;97: 2784–2790.CrossRefPubMedGoogle Scholar
  5. 5.
    Schmidt SM, Schag K, Muller MR, et al. Survivin is a shared tumorassociated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells. Blood. 2003;102: 571–576.CrossRefPubMedGoogle Scholar
  6. 6.
    Mesri M, Wall RW, Li J, Kim RW, Altieri DC. Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest. 2001;108:981–990.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kamihira S, Yamada Y, Hirakata Y, et al. Aberrant expression of caspase cascade regulatory genes in ATL: survivin is an important determinant for prognosis. Br J Haematol. 2001;114:63–69.CrossRefPubMedGoogle Scholar
  8. 8.
    Nakayama K, Kamihira S. Survivin an important determinant for prognosis in ATL: a novel biomarker in practical hemato-oncology. Leuk Lymphoma. 2002;43:2249–2255.CrossRefGoogle Scholar
  9. 9.
    Paydas S, Tanriverdi K, Yavuz S, Disel U, Sahin B, Burgut R. Survivin and aven: two distinct antiapototic signals in acute leukemias. Ann Oncol. 2003;14:1045–1050.CrossRefPubMedGoogle Scholar
  10. 10.
    Miyachi K, Sasaki K, Onodera S, et al. Correlation between survivin mRNA expression and lymph node metastasis in gastric cancer. Gastric Cancer. 2003;6:217–224.CrossRefPubMedGoogle Scholar
  11. 11.
    Hayashibara T, Yamada Y, Nakayama S, et al. Resveratol induces downregulation in survivin expression and apoptosis in HTLV-1- infected cell lines: a prospective agent for ATL chemotherapy. Nutr Cancer. 2002;44:192–201.CrossRefGoogle Scholar
  12. 12.
    Mori N, Yamada Y, Hatta T, et al. Expression of survivin in HTLV-1- infected T-cell lines and primary ATL cells. Biochem Biophys Res Commun. 2001;282:1110–1113.CrossRefGoogle Scholar
  13. 13.
    Sugahara K, Yamada Y, Hiragata Y, et al. Soluble and membrane isoforms of Fas/CD95 in fresh adult T-cell leukemia (ATL) cells and ATL-cell lines. Int J Cancer. 1997;72:128–132.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamada Y, Ohmoto Y, Yamamura M, et al. Plasma M-CSF as an indicator of response to chemotherapy in adult T cell leukemia patients. Leuk Lymphoma. 1996;22:457–461.CrossRefPubMedGoogle Scholar
  15. 15.
    Kamihira S, Dateki N, Sugahara K, et al. Significance of HTLV-1 proviral load quantification by real-time PCR as a surrogate marker for HTLV-1-infected cell count. Clin Lab Haematol. 2003; 25:111–117.CrossRefPubMedGoogle Scholar
  16. 16.
    Badran A, Yoshida A,Wano Y, et al. Expression of the antiapoptotic gene survivin in chronic myeloid leukemia. Anticancer Res. 2003;23:589–592.Google Scholar
  17. 17.
    Mori A,Wada H, Nishimura Y, Okamoto T, Takemoto Y, Kakishita E. Expression of the antiapoptosis gene survivin in human leukemia. Int J Hematol. 2002;75:161–165.CrossRefGoogle Scholar
  18. 18.
    Munzert G, Kirchner D, Stobbe H, et al. Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-_B/Rel-regulated inhibitors of apoptosis. Blood. 2002;100:3749–3756.CrossRefPubMedGoogle Scholar
  19. 19.
    Granziero L, Ghia P, Circosta P, et al. Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia. Blood. 2001;97: 2777–2783.CrossRefPubMedGoogle Scholar
  20. 20.
    Nakagawa Y, Yamaguchi S, Hasegawa M, et al. Differential expression of survivin in bone marrow cells from patients with acute lymphocytic leukemia. Leuk Res. 2004;28:487–494.CrossRefPubMedGoogle Scholar
  21. 21.
    Ullmannova V, Haskovec C. The use of housekeeping genes (HKG) as an internal control for the detection of gene expression by quantitative real-time RT-PCR. Folia Biol (Praha). 2003;49: 211–216.PubMedGoogle Scholar
  22. 22.
    Aerts JL, Gonzales MI, Topalian SL. Selection of appropriate control genes to assess expression of tumor antigens using real-time PCR. Biotechniques. 2004;36:84–86.CrossRefPubMedGoogle Scholar
  23. 23.
    Schnittger S, Weisser M, Schoch C, Hiddemann W, Haferiach T, Kern W. New score predicting for prognosis in PML-RAR+,AMLETO+, or CBFB-MYH11+ acute myeloid leukemia based on quantification of fusion transcripts. Blood. 2003;102:2746–2755.CrossRefPubMedGoogle Scholar
  24. 24.
    Watanabe T. HTLV-1 associated diseases. Int J Hematol. 1997;66: 257–278.CrossRefGoogle Scholar
  25. 25.
    Yasunaga J, Matsuoka M. Leukemogenesis of adult T-cell leukemia. Int J Hematol. 2003;78:312–320.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2004

Authors and Affiliations

  • Kazuyuki Sugahara
    • 1
  • Akiko Uemura
    • 1
  • Hitomi Harasawa
    • 1
  • Hiroshi Nagai
    • 1
  • Yoichi Hirakata
    • 1
  • Masao Tomonaga
    • 2
  • Kenn Murata
    • 1
  • Hiroshi Sohda
    • 1
  • Toru Nakagoe
    • 3
  • Sin-ichi Shibasaki
    • 3
  • Yasuaki Yamada
    • 1
  • Shimeru Kamihira
    • 1
  1. 1.Department of Laboratory MedicineNagasaki University Graduate School of Biomedical SciencesNagasaki CityJapan
  2. 2.Department of HematologyAtomic Disease InstituteJapan
  3. 3.First Department of SurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan

Personalised recommendations