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

Abstract

Survivin is a member of the inhibitor of apoptosis protein family. Survivin has splice variants with different biological functions associated with tumorigenesis. We investigated 134 non-small cell lung cancers (NSCLCs) to study the clinical significance of wildtype survivin, survivin-2B, and survivin-deltaEx3. Real-time PCR analyses were performed for their gene expressions. The subcellular localisation of survivin proteins was evaluated by immunohistochemistry. The Ki-67 proliferation index and the apoptotic index were also evaluated. The survivin-deltaEx3 gene expression was significantly higher in stage II -III than in stage I (P ¼ 0.0174), and significantly correlated with the nuclear pan-survivin expression (Po0.0001). The Ki-67 index was significantly higher in wild-type survivin-positive tumours (Po0.0001), survivin-deltaEx3-positive tumours (Po0.0001), and tumours with positive expression of the nuclear pansurvivin (P ¼ 0.0047). In contrast, the apoptotic index was significantly lower only in wild-type survivin-positive tumours (Po0.0001). Thus, the wild-type survivin gene expression was associated with apoptotic inhibition and tumour proliferation. Furthermore, the survivin-deltaEx3 gene expression was strongly associated with tumour proliferation, especially in advanced stage NSCLCs. In contrast, the survivin-2B gene expression did not correlate with tumour proliferation or tumour apoptosis.

Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia

“…1,2.24 In fact, some studies in solid tumors have demonstrated that nuclear survivin expression assessed by immunohistochemistry could be considered a favorable prognostic marker. 25 In hematologic malignancies, a differential compartmental localization of survivin has been assessed in mantle cell lymphoma 26 and lymphoid leukemia (acute and chronic) 27 by western blot and immunohistochemical studies. However, to the best of our knowledge only two studies have analyzed the global cellular expression of WT survivin and isoforms by reverse transcriptase polymerase chain reaction analysis in AML 8,28 and this is, therefore, the first description of the distribution of WT survivin and isoforms in nuclear and cytoplasmic compartments.…”

Wnt3 gene expression promotes tumor progression in non-small cell lung cancer

“…Therefore, in order to clarify the biological significance of the Wnt3 expression in NSCLCs, we investigated the Wnt3 expression in relation to Wnt targets, including c-Myc [9] and survivin [11,12]. In addition, we also evaluated the tumor proliferation rate and tumor apoptosis [17].…”

Intratumoral Wnt1 expression affects survivin gene expression in non-small cell lung cancer

“…At least 200 tumor cells were scored per x40 field. Regarding pansurvivin expression, the nuclear staining and the cytoplasmic staining in each section were evaluated, respectively, in a semi-quantitative manner which reflected both the intensity and percentage of cells staining at each intensity, as reported previously (23). The intensity was classified as 0 (no staining), +1 (weak staining), +2 (distinct staining), or +3 (very strong staining).…”

“…The statistical significances of survivin gene expression and protein expression of Wnt1 and Wnt5a in relation to several parameters were assessed by the t-test or the ¯2 test. The sample was classified as a survivin-high tumor when the standardized survivin gene expression was >1.0, because a standardized survivin gene expression cut-off line of 1.0 demonstrated the greatest significance in relation to the apoptotic index and the Ki-67 proliferation index (23). The sample was classified as a Wnt1-high tumor when the percentage of Wnt1-positive tumor cells was >50%, and the sample was classified as a Wnt5a-high tumor when the percentage of Wnt5a-positive tumor cells was >30%, as reported previously (24,25).…”

“…This study therefore investigated the survivin gene expression in relation to the intratumoral expression of Wnt1 (a novel member of the canonical Wnt pathway) (21) and Wnt5a (a novel member of the non-canonical Wnt pathway) in NSCLC patients (22). (23). The total cellular RNA was extracted from frozen tissue specimens by the acid guanidinium thiocyanate procedure.…”