Abstract:
N-myc downstream-regulated gene 2 (NDRG2) has been recognised as a negative regulator of the progression of numerous tumours, yet its specific role in small-cell lung carcinoma (SCLC) is not fully understood. The purpose of the current study was to investigate the biological role and mechanism of NDRG2 in SCLC. Initial investigation using the Gene Expression Omnibus (GEO) dataset revealed marked downregulation of NDRG2 transcripts in SCLC. The decreased abundance of NDRG2 in SCLC was verified by examining clinical specimens. Increasing NDRG2 expression in SCLC cell lines caused significant changes in cell proliferation, cell cycle progression, colony formation, and chemosensitivity. NDRG2 overexpression decreased the levels of phosphorylated PTEN, AKT and mTOR. In PTEN-depleted SCLC cells, the upregulation of NDRG2 did not result in any noticeable impact on AKT or mTOR activation. Additionally, the reactivation of AKT reversed the antitumour effects of NDRG2 in SCLC cells. Notably, increasing NDRG2 expression retarded the growth of SCLC cell-derived xenografts in vivo. In conclusion, NDRG2 serves as an inhibitor of SCLC, and its cancer-inhibiting effects are achieved through the suppression of AKT/mTOR via the activation of PTEN. This work suggests that NDRG2 is a potential druggable target for SCLC treatment.
摘要:
N-myc下游调节基因2(NDRG2)已被认为是许多肿瘤进展的负调节因子。但其在小细胞肺癌(SCLC)中的具体作用尚不完全清楚.本研究的目的是探讨NDRG2在SCLC中的生物学作用及其机制。使用基因表达综合(GEO)数据集的初步研究揭示了SCLC中NDRG2转录物的显著下调。通过检查临床标本证实了SCLC中NDRG2丰度的降低。在SCLC细胞系中NDRG2表达的增加引起细胞增殖的显著变化,细胞周期进程,菌落形成,和化学敏感性。NDRG2过表达降低了磷酸化PTEN的水平,AKT和mTOR。在PTEN耗尽的SCLC细胞中,NDRG2的上调对AKT或mTOR激活没有任何明显影响.此外,AKT的再激活逆转了NDRG2在SCLC细胞中的抗肿瘤作用.值得注意的是,NDRG2表达的增加阻碍了SCLC细胞来源的异种移植物在体内的生长。总之,NDRG2作为SCLC的抑制剂,其抑癌作用是通过激活PTEN抑制AKT/mTOR实现的。这项工作表明NDRG2是SCLC治疗的潜在药物靶标。