Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
Biochem Biophys Res Commun. 2018 Oct 2;504(2):525-531. doi: 10.1016/j.bbrc.2018.08.181. Epub 2018 Sep 7.
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 PDGFRα in pathogenesis, progression and prognisis of NKTCL. Firstly, we performed immunohistochemical staining, qRT-PCR and western blotting to determine PDGFRα expression in formalin-fixed, paraffin-embedded tissue sections from 78 NKTCL cases and in cell lines. Secondly, correlations between PDGFRα expression and NKTCL clinical parameters and prognosis were analysed. Moreover, a biological assessment of PDGFRα 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 PDGFRα was significantly higher in NKTCL tissues compared to the reactive lymphoid hyperplasia of the nasopharynx (P = 0.028). High PDGFRα expression was strongly associated with a high LDH level (P = 0.028) and III-IV stage (P = 0.013). NKTCL patients with high PDGFRα expression displayed a reduced median overall survival time and progression-free survival time when compared with those with low PDGFRα expression (P = 0.011, P = 0.005, respectively). Cox multivariate analysis showed that III-IV stage (P = 0.024) and high PDGFRα 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 PDGFRα 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.
鼻型自然杀伤/T 细胞淋巴瘤（NKTCL）是一种侵袭性强、预后差的非霍奇金淋巴瘤（NHL）亚型。血小板衍生生长因子受体（PDGFRs）及其配体（PDGFs）在各种肿瘤的血管生成、癌细胞增殖、存活、迁移和不良预后中发挥重要作用。然而，PDGFRs 在 NKTCL 中的意义尚不清楚。本研究旨在探讨 PDGFRα 在 NKTCL 发病机制、进展和预后中的重要作用。首先，我们通过免疫组织化学染色、qRT-PCR 和 Western blot 检测了 78 例 NKTCL 病例的福尔马林固定石蜡包埋组织切片和细胞系中 PDGFRα 的表达。其次，分析了 PDGFRα 表达与 NKTCL 临床参数和预后的相关性。此外，通过增殖试验、细胞周期评估和流式细胞术分析检测了两种 NKTCL 细胞系中 PDGFRα 阻断的生物学效应。此外，我们还在 NKTCL 小鼠模型中检测了伊马替尼的体内活性。我们发现 PDGFRα 的表达在 NKTCL 组织中明显高于鼻咽反应性淋巴组织增生（P=0.028）。高 PDGFRα 表达与高 LDH 水平（P=0.028）和 III-IV 期（P=0.013）密切相关。与低 PDGFRα 表达的患者相比，高 PDGFRα 表达的 NKTCL 患者的中位总生存时间和无进展生存时间明显缩短（P=0.011，P=0.005）。Cox 多因素分析显示，III-IV 期（P=0.024）和高 PDGFRα 表达（P=0.003）是 NKTCL 患者的独立预后因素。两种 NKTCL 细胞系的生物学评估试验表明，一种特定的 PDGFR 拮抗剂伊马替尼抑制细胞活力，阻滞 G0/G1 期细胞周期进展并诱导细胞凋亡。同样，体内试验表明伊马替尼可延缓小鼠模型肿瘤生长。总之，NKTCL 肿瘤细胞具有明显的 PDGFRα 表达，可作为候选预后标志物。PDGFR 拮抗剂对 NKTCL 具有显著的生物学效应，可能是治疗 NKTCL 的有效治疗药物。
