Shanxi Provincial People's Hospital, Taiyuan 030012, China.
Key Laboratory of Central Nervous System Injury Research, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China.
Medicina (Kaunas). 2023 Feb 15;59(2):373. doi: 10.3390/medicina59020373.
: Non-functioning pituitary neuroendocrine tumors (NF-PitNETs) represent a heterogeneous tumor type that lacks effective medical treatment. MDM2, the main negative regulator of p53, binds to and forms a stable complex with p53 to regulate its activity. In this study, we measured the expression levels and role of MDM2 in non-functioning PitNET patients' combined clinical features and investigated the effect of etoposide on the cell bioactivity of the GT1-1 cell line in vivo and in vitro. : RT-PCR and immunochemistry measured the expression levels and role of MDM2 in 103 NF-PitNET patients' combined clinical features. Cell proliferation, migration, colony and apoptosis experiments measured the effect of etoposide on the GT1-1 cell line in vivo and in vitro. : There was more invasive behavior ( = 0.013) in patients with high MDM2, who were also younger ( = 0.007), were more frequently female ( = 0.049) and had larger tumor sizes ( = 0.018) compared with patients with low MDM2. Patients with high p53 were younger ( = 0.017) and had larger tumor sizes ( = 0.034) compared with patients with low p53. Univariate ( = 0.018) and multivariate ( = 0.023) Cox regression analysis showed that MDM2 was the independent factor for invasive behavior in NF-PitNET patients. Log-rank analysis showed that the average progression-free survival (PFS) time in the low MDM2 patients was longer than that in the high MDM2 patients ( = 0.044). Functional studies indicated that etoposide inhibited cell proliferation and cell migration and induced apoptosis in p53 independence in GT1-1 cells. Furthermore, etoposide significantly inhibited the growth of GT1-1-xenograft in BALB/c nude mice. The tumor growth inhibition rate of etoposide was 67.4 ± 4.6% after 14 d of treatment, which suggested the anti-tumor activity of etoposide. : MDM2 played the role of tumorigenesis of NF-PitNET in a p53 independence manner, and an MDM2 inhibitor could be a potential choice for the treatment of NF-PitNET patients.
无功能性垂体神经内分泌肿瘤（NF-PitNET）是一种缺乏有效治疗方法的异质性肿瘤类型。MDM2 是 p53 的主要负调控因子，它与 p53 结合并形成稳定的复合物，以调节其活性。在这项研究中，我们测量了 MDM2 在非功能性 PitNET 患者的联合临床特征中的表达水平和作用，并研究了依托泊苷对 GT1-1 细胞系在体内和体外的细胞生物活性的影响。
使用 RT-PCR 和免疫组织化学方法测量了 103 例 NF-PitNET 患者联合临床特征中 MDM2 的表达水平和作用。使用细胞增殖、迁移、集落和凋亡实验测量了依托泊苷对 GT1-1 细胞系在体内和体外的作用。
与 MDM2 低表达的患者相比，MDM2 高表达的患者具有更具侵袭性的行为（ = 0.013），年龄更小（ = 0.007），女性更常见（ = 0.049），肿瘤体积更大（ = 0.018）。与 p53 低表达的患者相比，p53 高表达的患者年龄更小（ = 0.017），肿瘤体积更大（ = 0.034）。单因素（ = 0.018）和多因素（ = 0.023）Cox 回归分析显示，MDM2 是 NF-PitNET 患者侵袭性行为的独立因素。对数秩分析显示，低 MDM2 患者的平均无进展生存期（PFS）时间长于高 MDM2 患者（ = 0.044）。功能研究表明，依托泊苷抑制了 GT1-1 细胞中 p53 非依赖性的细胞增殖和细胞迁移，并诱导了细胞凋亡。此外，依托泊苷显著抑制了 BALB/c 裸鼠 GT1-1-xenograft 的生长。依托泊苷治疗 14 天后，肿瘤生长抑制率为 67.4 ± 4.6%，提示依托泊苷具有抗肿瘤活性。
MDM2 以 p53 非依赖性的方式发挥 NF-PitNET 的致癌作用，MDM2 抑制剂可能是治疗 NF-PitNET 患者的潜在选择。
