Differential expression of survivin-2B and survivin-ΔEx3 is inversely associated with disease relapse and patient survival in non-small-cell lung cancer (NSCLC)

Abstract

SummaryAlthough it was observed that inhibition of the antiapoptotic protein survivin expression in lung cancer cells induces apoptosis, the expression and role of survivin variants (survivin-2B and survivinΔEx3) in lung cancer have not yet been characterized. We analyzed 24 non-small-cell lung cancer (NSCLC) samples by semi-quantitative RT-PCR. Surprisingly, our results revealed that high-level expression of survivin-2B is significantly associated with the patient category of "no relapse and alive" (p-value < 0.0001). In contrast, high-level expression of survivin-ΔEx3 is highly associated with the patient category of "relapse and dead" (p-value < 0.0001). Consistent with this observation, exogenous expression of survivin-2B in A549 lung cancer cells inhibited cell growth, disrupted the mitochondria potential, and induced apoptotic cell death, while expression of survivin-ΔEx3 protected the mitochondria potential and facilitated cell survival. These findings provide evidence that survivin-2B and survivin-ΔEx3 play opposite roles in disease relapse and NSCLC cell survival, which is likely through the differential modulation of mitochondrial potential. Thus, controlling the differential expression of survivin-2B and survivin-ΔEx3 may represent novel approaches for cancer therapeutics in NSCLC. KeywordsSurvivin-2B; Survivin-ΔEx3; Non-small-cell lung cancer

The clinical significance of splice variants and subcellular localisation of survivin in non-small cell lung cancers

“…On the other hand, previous immunohistochemical studies revealed the nuclear expression of survivin proteins also to be associated with tumour cell proliferation and a poor prognosis in cancer patients, as was also shown in the present study, while the cytoplasmic expression of survivin proteins was not (Martinez et al, 2004;Huang et al, 2005;Ling et al, 2005;Shinohara et al, 2005;Taubert et al, 2005). These studies were performed using antibodies against pan-survivin, which cannot distinguish wildtype survivin from other spliced variants.…”

“…In fact, previous clinical studies also revealed the survivindeltaEx3 expression to be associated with a high proliferation rate (Takashima et al, 2005). Recent studies have revealed that the survivin-deltaEx3 overexpression is a significant poor prognostic factor in cancer patients, including NSCLCs (Ling et al, 2005;Taubert et al, 2005). Furthermore, the present study found the survivin-deltaEx3 gene expression to be significantly higher in advanced-stage NSCLCs.…”

“…Previous clinical studies have reported the survivin expression to be associated with tumour cell proliferation, apoptotic inhibition, and a poor prognosis in various human cancers, including NSCLCs (Martinez et al, 2004;Shinohara et al, 2005). However, only a few clinical reports studied these splice variants of survivin in human cancers (Mahotka et al, 2002a;Meng et al, 2004;Ling et al, 2005;Taubert et al, 2005). Therefore, to clarify the clinical significance of these splice variants of survivin in NSCLCs, we performed the present study on the gene expressions of wild-type survivin, survivin-2B, and survivin-deltaEx3 in relation to the subcellular localisation of survivin proteins, tumour cell proliferation, and apoptosis.…”

The Effect of Survivin on Multidrug Resistance Mediated by P-Glycoprotein in MCF-7 and Its Adriamycin Resistant Cells

“…Survivin is a protein which travels frequently between the cytoplasm and nuclear locations and it requires an active temperature-sensitive import mechanism. Growing evidence has indicated that there is mitochondrial localization of survivin in cancer cells, 28,29) and the intracellular transport of survivin is very important for the antiapoptosis effects of the protein. 29,30) Taking all these together, the overexpression of Pgp may mediate intracellular protein transport, which might facilitate the transport of survivin from one location to another and induce hyperfunctioning of the protein not only in anti-apoptosis but also in chemoresistance.…”

Survivin: Identification of Selective Functional Signaling Pathways inTransformed Cells and Identification of a New Splice Variant with Growth Survival Activity

“…Spliced variants identified to date include Survivin 2 (Caldas et al, 2005;Mahotka et al, 2002) , 2B, Ex3 (Ling et al, 2005;Mahotka et al, 1999;Mahotka et al, 2002;Song & Wu, 2005) and 3B (Badran et al, 2004), and some of these variants have been evaluated for their anti-or pro-apoptotic function and ability to interact with wild-type Survivin and other chromosomal passenger proteins (CPC) in some model systems. More recently, several new Survivin splice variants were found in the expressed sequence tag (est) database or described based on RT-PCR using RNA from Molt-4 cells (Li & Ling, 2006;Mola et al, 2007), however the biological functions of these new variants are not known.…”