Survivin is a prognostic marker and therapeutic target for extranodal, nasal-type natural killer/T cell lymphoma

Abstract

Background: The relationship between survivin and extranodal, nasal-type natural killer/T cell lymphoma (ENKTCL) was unclearly established yet. We here studied the potential prognostic roles of survivin and its implication as a target in ENKTCL therapy.

Methods: ENKTCL patients' peripheral blood were collected and tested by ELISA. ENKTCL cell lines were cultured with or without survivin inhibitor and tested by MTT and Flow cytometry. According to the gene expression profiles from the ArrayExpress Archive under E-TABM-702, survivin co-regulated cluster was established by Coupled Two-way Clustering Algorithm.

Results: Seventeen point six percent of total 17 ENKTCL patients were serum survivin-positive. These patients had poorer outcome than that of negative cases (P<0.01). Analysis of survivin co-regulation genes in ENKTCL revealed that survivin was significantly involved in pluripotency, drug resistance, cell cycle and proliferation, indicating that it should be one of key regulators in ENKTCL and might be a latent therapeutic target. Our results just showed that YM155, a survivin inhibitor, had strong anti-tumor effect on ENKTCL cell lines in a dose dependent manner. It increased sub-G1 phase population and reduced G1- and G2-M phase populations (P<0.05). In addition, combining YM155 with DDP induced a larger decrease in cell viability than either agent alone and had a higher inhibition rate than Bliss index, suggesting their synergistic inhibition.

Conclusions: We concluded that survivin was a potential prognostic marker and a critical regulatory molecule in the pathological process of ENKTCL. It would be a promising target in drugs discovery for ENKTCL therapy.

Keywords: Extranodal, nasal-type natural killer/T cell lymphoma (ENKTCL); prognosis; survivin; therapeutic target.

Figure 1

Survival curve of ENKTCL patients. (A) Survival curve for all patients; (B) survival comparison between patients with survivin positive (survivin+) and patients with survivin negative (survivin−).

Figure 2

Survivin co-regulated gene set. (A) Expression Heatmap of BIRC5-coregulated Cluster based on the coupled two-way clustering algorithm; (B) samples’ relationship by the principle component analysis (ReNK: Resting NK-cell; AcNK: Activated NK-cell).

Figure 3

Anti-tumor effect of YM155 alone. (A) The curve of inhibition rate followed by the varieties of YM155 concentrations (0, 3.125, 6.25, 12.5, 25, 50, 100 and 200 nm/L); (B) the curve of inhibition rate followed by time changes (6, 12, 24, 48 and 72 h); (C) after YM155 treatment for 24 h, cell-cycle distribution was detected via flow cytometry; (D) the difference of population in different cell-cycle stages compared with control (*, P<0.05).

Figure 4

The effect after YM155 combined with DDP treatment for 24 h. Each bar represents the mean ± SD of inhibition rate from three separate experiments. The bliss index was showed as dashed line. DDP vs. DDP+YM155: *, P<0.001; YM155 vs. DDP+YM155: ^, P<0.01.

Figure S1

Expression heatmap of 11,254 genes across 51 samples. PTCL, peripheral T-cell lymphoma; NOS, not otherwise specified.