Chen Zhenfa, Wang Ting, Li Cui, Zhang Wei, Huang Wenbin, Xue Jun, Wang Jundong, Li Shufeng
Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Biochemistry and Molecular Biology, Medical School of Southeast University, Nanjing 210009, China.
Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
J Cancer. 2023 Jul 16;14(12):2289-2300. doi: 10.7150/jca.85906. eCollection 2023.
GINS1 is overexpressed in several types of cancers including leukemia and linked to poor outcomes. However, GINS1 remains poorly investigated in DLBCL (diffuse large B-cell lymphoma). This project aimed to explore the expression, functions and regulation of GINS1 in DLBCL. In this study, through analysis of clinical specimens from DLBCL patients, we uncovered that GINS1 was upregulated in DLBCL. By EMSA, ChIP and luciferase reporter assays, it was found that FOXP1 transcriptionally activated GINS1 expression by directly binding to the promoter region of the GINS1 gene. Western blotting and RT-PCR also revealed that GINS1 expression positively correlated with FOXP1 in human DLBCL specimens and cell lines. In an in vivo xenograft lymphoma mouse model, the FOXP1/GINS1 regulatory axis was also validated. Moreover, with CCK8 cell proliferation assays and colony formation assay, elevated GINS1 expression was found to be associated with doxorubicin resistance in lymphoma cells. Our findings showed that the FOXP1-GINS1 axis played a critical role in DLBCL development and doxorubicin resistance, and targeting the FOXP1-GINS1 axis could be a potential therapeutic approach for DLBCL treatment.
GINS1在包括白血病在内的多种癌症中过度表达，并与不良预后相关。然而，GINS1在弥漫性大B细胞淋巴瘤（DLBCL）中的研究仍较少。本项目旨在探讨GINS1在DLBCL中的表达、功能及调控机制。在本研究中，通过对DLBCL患者临床标本的分析，我们发现GINS1在DLBCL中上调。通过电泳迁移率变动分析（EMSA）、染色质免疫沉淀（ChIP）和荧光素酶报告基因检测，发现FOXP1通过直接结合GINS1基因的启动子区域转录激活GINS1的表达。蛋白质免疫印迹法（Western blotting）和逆转录-聚合酶链反应（RT-PCR）也显示，在人DLBCL标本和细胞系中，GINS1的表达与FOXP1呈正相关。在体内异种移植淋巴瘤小鼠模型中，FOXP1/GINS1调控轴也得到了验证。此外，通过CCK8细胞增殖试验和集落形成试验，发现GINS1表达升高与淋巴瘤细胞对阿霉素耐药有关。我们的研究结果表明，FOXP1-GINS1轴在DLBCL的发生发展和阿霉素耐药中起关键作用，靶向FOXP1-GINS1轴可能是DLBCL治疗的一种潜在治疗方法。
