Survivin, Survivin-2B, and Survivin-deItaEx3 expression in medulloblastoma: biologic markers of tumour morphology and clinical outcome

Abstract

Survivin is an apoptotic inhibitor that is expressed at high levels in a variety of malignancies. Survivin has four known alternative splice forms (Survivin, Survivin-2B, Survivin-deltaEx3, and Survivin-3B), and the recent literature suggests that these splice variants have unique functions and subcellular localisation patterns. We evaluated 19 fresh-frozen paediatric medulloblastomas for the expression of three Survivin isoforms by quantitative PCR. Survivin was most highly expressed when compared with normal cerebellar tissue. We also investigated Survivin protein expression in 40 paraffin-embedded paediatric medulloblastoma tumours by immunohistochemistry. We found a statistically significant association between the percentage of Survivin-positive cells and histologic subtype, with the large-cell-anaplastic variant expressing Survivin at higher levels than the classic subtype. We also found a statistically significant relationship between the percent of Survivin-positive cells in the tumours and clinical outcome, with higher levels of Survivin correlating with a worse prognosis. In summary, our study demonstrates a role for Survivin as a marker of tumour morphology and clinical outcome in medulloblastoma. Survivin may be a promising future prognostic tool and potential biologic target in this malignancy.

Elevated expression of survivin-splice variants predicts a poor outcome for soft-tissue sarcomas patients

“…The calculation of the expression ratio between tumour and normal tissue with an increase of 18.6-, 33.5-, and 13.4-fold for survivin, survivin-DEx3 and survivin-2B, respectively, makes this increase even clearer. The predominant expression of the wild-type variant of survivin is in agreement with results for gastric cancer, renal cell carcinomas, leukemias, breast cancer and medulloblastomas (Krieg et al, 2002;Mahotka et al, 2002a;Nakagawa et al, 2004;Fangusaro et al, 2005;Ryan et al, 2005).…”

“…These splice variants are functionally different because only survivin-DEx3 has antiapoptotic properties like survivin, whereas the antiapoptotic potential of survivin-2B is markedly reduced (Mahotka et al, 1999(Mahotka et al, , 2002b. Expression of survivin splice variants was investigated for different malignant tumours (Islam et al, 2000;Hirohashi et al, 2002;Krieg et al, 2002;Mahotka et al, 2002a;O'Driscoll et al, 2003;Yamada et al, 2003;Fangusaro et al, 2005;Ryan et al, 2005). We could show that whole survivin mRNA expression was significantly correlated to a poor survival of soft tissue sarcoma patients (STS) (Kappler et al, 2001;Wu¨rl et al, 2002).…”

Dissecting the role of endothelial SURVIVIN ΔEx3 in angiogenesis

“…In this analysis, Survivin ⌬Ex3 localized to areas of the tissue that were distinct from that of the Survivin protein. While Survivin itself was expressed in more than 50% of tumor cells as previously shown, 16 Survivin ⌬Ex3 was not detected within the tumor cells themselves but was exclusively located within the vascular endothelial cells of the tumor ( Figure 1A-B). Although previous studies suggested that Survivin ⌬Ex3 is also expressed within tumor cells, 16 as determined by quantitative PCR analysis of RNA isolated from a tumor cell line or from a human tumor biopsy, the protein analyses performed here did not reveal prominent expression within tumor cells.…”

“…16 One hundred and fifty micrograms of protein extract from ependymoma and normal brain ependyma and 10 g of protein extract from transfected HeLa cells were separated on an 18% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel and transferred onto a nitrocellulose membrane. The membrane was immunoprobed as previously described.…”

Characterisation of the anti-apoptotic function of survivin-ΔEx3 during TNFα−mediated cell death

“…The open reading frame of survivin-DEx3 encodes a protein with an interrupted BIR domain and a unique 63 amino-acid long Cterminal tail (Mahotka et al, 1999). Overexpression of survivinDEx3 is observed in several human malignancies, including renal cell carcinoma, breast cancer, gastric carcinoma, and medulloblastoma (Krieg et al, 2002;Mahotka et al, 2002a;Fangusaro et al, 2005;Ryan et al, 2005). In addition, expression of survivin and survivin-DEx3 remains constant in different stages of cancer (Krieg et al, 2002).…”