【摘要】 目的：探究弥漫大B细胞淋巴瘤阿霉素耐药的关键信号通路及转录调控因子。方法：用阿霉素浓度梯度逐步递增的方法诱导筛选出人DLBCL耐阿霉素细胞株，以空白组细胞以及含有0.5%DMSO干预组细胞为对照，进行转录水平测序。对测序获得的基因表达谱进行差异分析，获得潜在的阿霉素耐药相关基因。对耐药相关基因进行信号通路分析，结合公共数据库预测调控耐药相关基因的上游转录因子，并对关键的转录因子做进一步验证。结果：测序数据分析得到900个耐药相关基因，信号通路分析发现这些耐药基因主要富集在PI3K-AKT通路中。转录因子FOXM1可调控68.3%的耐药相关基因。FOXM1可能调控富集在PI3K-AKT通路中的耐药相关基因。非霍奇金淋巴瘤细胞中沉默FOXM1的表达引起广泛的基因表达异常，这些异常表达的基因主要富集在PI3K-AKT通路中。整合4个数据集证明FOXM1在DLBCL中呈高表达；高表达FOXM1与患者预后不良有关（HR=1.36）。结论：FOXM1可能通过影响PI3K-AKT通路介导DLBCL细胞产生阿霉素耐药。更多还原

【Abstract】 Objective: To investigate the key signaling pathways and transcriptional regulators of doxorubicin resistance in diffuse large B-cell lymphoma(DLBCL). Methods: Doxorubicin-resistant human DLBCL cell lines were screened by gradual increments of doxorubicin concentration, cells in the blank group and the group undergoing 0.5% dimethyl sulfoxide(DMSO) intervention were taken as controls, and RNA sequencing was performed. The gene expression profiles obtained by sequencing were analyzed differentially to obtain potential doxorubicin resistance-associated genes. Signaling pathway analysis of resistance-associated genes was performed to predict the upstream transcription factors regulating resistance-associated genes in combination with public databases, and further validation of key transcription factors was performed. Results: Sequencing data analysis yielded 900 drug resistance-associated genes, and signaling pathway analysis revealed that these resistance genes were mainly enriched in the PI3K/AKT pathway. The transcription factor FOXM1 regulated 68.3%of the drug resistance-associated genes, and FOXM1 might regulate drug resistance-associated genes enriched in the PI3K/AKT pathway. Silencing FOXM1 expression in non-Hodgkin’s lymphoma cells caused a wide range of gene expression abnormalities, and these abnormally expressed genes were mainly enriched in the PI3K/AKT pathway. Integration of four datasets demonstrated that FOXM1 was highly expressed in DLBCL; high FOXM1expression was associated with poor patient prognosis(HR = 1.36). Conclusion: FOXM1 may mediate adriamycin resistance in DLBCL cells by affecting the PI3K/AKT pathway.更多还原