无功能垂体腺瘤中 MDM2 的表达及临床意义。

Expression and Clinical Significance of MDM2 in Non-Functioning PitNETs.

机构信息

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.

出版信息

Medicina (Kaunas). 2023 Feb 15;59(2):373. doi: 10.3390/medicina59020373.

DOI:10.3390/medicina59020373

PMID:36837574

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9963423/

Abstract

: 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.

摘要

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。