【摘要】 目的:探究核输出蛋白1(XPO1)在初发成人弥漫性大B细胞淋巴瘤(DLBCL)中的表达情况及临床意义，并进一步探索其功能机制。方法:采用免疫组化方法检测93例DLBCL和30例淋巴结反应增生患者XPO1的表达水平。构建预后风险模型以寻找DLBCL患者生存预后相关基因。通过细胞增殖、凋亡和细胞周期实验，探索XPO1抑制剂(KPT-8602)及XPO1敲降对DLBCL细胞的影响。通过分析公共数据库转录组测序结果，寻找XPO1相关差异表达基因(DEG)。结果:免疫组化结果表明，XPO1在DLBCL中的表达水平明显高于对照组(P<0.05)。与XPO1低表组相比，XPO1高表组患者的预后明显更差(P<0.05)。通过构建预后风险模型发现XPO1及核浆转运通路(NTP)中的14个基因可能是DLBCL患者的高危预后因素。此外，在两种DLBCL细胞系Farage及SU-DHL-4中，KPT-8602及XPO1敲降可以抑制DLBCL细胞的增殖、促进凋亡和阻滞细胞周期。基于公共数据库DLBCL转录组测序结果，将患者分为XPO1高表达和低表达组，分析两组的DEG,提示MYBL1可能是XPO1的下游信号分子。抑制XPO1功能或者降低XPO1表达均可以显著降低MYBL1的表达。结论:XPO1在DLBCL患者中的表达水平明显增高，且与不良预后相关。XPO1可能通过激活XPO1/MYBL1信号通路从而在DLBCL中发挥促肿瘤作用，XPO1抑制剂可能是初发DLBCL患者的一种潜在治疗选择。更多还原

【Abstract】 Objective: To explore the expression and clinical significance of XPO1 in newly diagnosed adult diffuse large B-cell lymphoma(DLBCL), and further investigate its functional mechanism. Methods: Immunohistochemical testing was conducted for XPO1 expression in 93 cases of DLBCL and 30 cases of reactive lymphoid hyperplasia. A risk model was construed to find survival related genes in DLBCL patients. Cell proliferation, apoptosis, and cell cycle assays were performed to explore the effect of XPO1 inhibitor(KPT-8602) and XPO1 knockdown. Differential expression gene(DEG) was examined based on the transcriptomes. Results: The expression of XPO1 in DLBCL patients was higher than that of the controls. Compared with XPO1low-expression group, XPO1 high-expression group had a worse prognosis. The constructed risk model indicated that XPO1 and 14 genes in nucleocytoplasmic transport pathway(NTP) might be potential prediction marker of adverse outcome in DLBCL. Moreover, KPT-8602 as well as the XPO1 knockdown could inhibit cell proliferation, promote apoptosis, and induce cell cycle arrest in two DLBCL cell lines, Farage and SU-DHL-4. Based on the gene expression profiling in the datasets of DLBCL, patients were classified into XPO1-high and XPO1-low expression groups, and the MYBL1 was identified as the down-stream effector of XPO1. Inhibiting the function of XPO1 or reducing its expression can significantly decrease the expression of MYBL1. Conclusion: XPO1 is highly expressed in DLBCL, which is associated with poor prognosis. The oncogenic roles of the new XPO1/MYBL1 signaling are identified in DLBCL and XPO1 inhibitor may be a potential option for newly-diagnosed DLBCL patients.更多还原