Platelet-derived growth factor receptor alpha (PDGFR alpha) is overexpressed in NK/T-cell lymphoma and mediates cell survival

摘要

Nasal-type natural killer/T-cell lymphoma (NKTCL) is a subtype of non-Hodgkin lymphoma (NHL) that is clinically aggressive and has a poor prognosis. Platelet-derived growth factor receptors (PDGFRs) and their ligands (PDGFs) play important roles in angiogenesis, cancer cell proliferation, survival, migration and poor prognosis in various tumours. However, the significance of PDGFRs in NKTCL remains unknown. Herein, the present study aimed to investigate the important role of PDGFR alpha in pathogenesis, progression and prognisis of NKTCL. Firstly, we performed immunohistochemical staining, qRT-PCR and western blotting to determine PDGFR alpha expression in formalin-fixed, paraffin-embedded tissue sections from 78 NKTCL cases and in cell lines. Secondly, correlations between PDGFR alpha expression and NKTCL clinical parameters and prognosis were analysed. Moreover, a biological assessment of PDGFR alpha blockade in two NKTCL cell lines was conducted through proliferation assay, cell-cycle evaluation and apoptosis detection by flow cytometry analyses. Furthermore, we detected in vivo activity of imatinib in mouse model of NKTCL. We found that the expression of PDGFR alpha was significantly higher in NKTCL tissues compared to the reactive lymphoid hyperplasia of the nasopharynx (P = 0.028). High PDGFR alpha expression was strongly associated with a high LDH level (P = 0.028) and III-IV stage (P = 0.013). NKTCL patients with high PDGFR alpha expression displayed a reduced median overall survival time and progression-free survival time when compared with those with low PDGFR alpha expression (P = 0.011, P = 0.005, respectively). Cox multivariate analysis showed that III-IV stage (P = 0.024) and high PDGFR alpha expression (P = 0.003) were independent prognostic factors in NKTCL patients. Biological assessment assays in two NKTCL cell lines revealed that a specific PDGFR antagonist, imatinib, inhibited cell viability, blocked cell cycle progression at G0/G1 stage and induced apoptosis. Similarly, the in vivo assay showed that imatinib delayed mouse model tumour growth. In conclusion, NKTCL tumour cells have prominent PDGFR alpha expression, which can serve as a candidate prognostic marker. PDGFR antagonists have significant biological effect on NKTCL and may be useful therapeutic agents for treatment of NKTCL. (C) 2018 Elsevier Inc. All rights reserved.