Abstract：
Diffuse large B-cell lymphoma (DLBCL) represents the most common tumor in non-Hodgkin\'s lymphoma. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor highly expressed in healthy tissues but downregulated in many cancers. Although cell proliferation-related metabolism rewiring has been well characterized, less is known about the mechanism of metabolic changes with DLBCL. Herein, we investigated the expressions of NDRG2, MYC and Myc-interacting zinc finger protein 1 (MIZ-1) in seven human lymphoma (mostly DLBCLs) cell lines. NDRG2 expression was inversely correlated with the expressions of MYC and MIZ-1. Further, we explored the regulatory mechanism and biological functions underlying the lymphomagenesis involving NDRG2, MYC and MIZ-1. MYC and MIZ-1 promoted DLBCL cell proliferation, while NDRG2 induced apoptosis in LY8 cells. Moreover, NDRG2 methylation was reversed by the 5-Aza-2\'-deoxycytidine (5-Aza-CDR) treatment, triggering the downregulation of MYC and inhibiting DLBCL cell survival. MYC interacts with NDRG2 to regulate energy metabolism associated with mTOR. Remarkably, supporting the biological significance, the converse correlation between NDRG2 and MYC was observed in human DLBCL tumor tissues (R = -0.557). Bioinformatics analysis further validated the association among NDRG2, MYC, MIZ-1, mTOR, and related metabolism genes. Additionally, NDRG2 (P = 0.001) and MYC (P < 0.001) were identified as promising prognostic biomarkers in DLBCL patients through survival analysis. Together, our data demonstrate that the MYC/MIZ-1 complex interplays with NDRG2 to influence the proliferation and apoptosis of DLBCL cells and show the characterizations of NDRG2, MYC and MIZ-1 for metabolism features and prediction prognosis in DLBCL.
摘要：
弥漫性大B细胞淋巴瘤(DLBCL)是非霍奇金淋巴瘤中最常见的肿瘤。N-Myc下游调节基因2（NDRG2）是一种在健康组织中高表达但在许多癌症中下调的肿瘤抑制因子。尽管细胞增殖相关的代谢重新连接已得到很好的表征，关于DLBCL代谢变化的机制知之甚少。在这里，我们研究了NDRG2，MYC和Myc相互作用锌指蛋白1（MIZ-1）在7种人类淋巴瘤（主要是DLBCLs）细胞系中的表达。NDRG2的表达与MYC和MIZ-1的表达呈负相关。Further,我们探讨了NDRG2,MYC和MIZ-1参与的淋巴生成的调节机制和生物学功能.MYC和MIZ-1促进DLBCL细胞增殖，而NDRG2诱导LY8细胞凋亡。此外，NDRG2甲基化被5-Aza-2'-脱氧胞苷（5-Aza-CDR）处理逆转，触发MYC下调并抑制DLBCL细胞存活。MYC与NDRG2相互作用以调节与mTOR相关的能量代谢。值得注意的是,支持生物学意义，在人DLBCL肿瘤组织中观察到NDRG2和MYC之间的负相关（R=-0.557）。生物信息学分析进一步验证了NDRG2、MYC、MIZ-1,mTOR,和相关的代谢基因。此外,通过生存分析，NDRG2（P=0.001）和MYC（P<0.001）被确定为DLBCL患者有希望的预后生物标志物。一起,我们的数据表明,MYC/MIZ-1复合物与NDRG2相互作用,影响DLBCL细胞的增殖和凋亡,并显示了NDRG2,MYC和MIZ-1在DLBCL代谢特征和预测预后方面的特征.
