| 王 佩,曹田宇,周 云.FOXJ2转录激活胃癌细胞PD-L1表达并抑制T细胞抗肿瘤免疫的研究[J].中国肿瘤,2021,30(12):933-941. |
| FOXJ2转录激活胃癌细胞PD-L1表达并抑制T细胞抗肿瘤免疫的研究 |
| FOXJ2 Inhibits T Cells Anti-tumor Immunity Through Transcriptional Activation of PD-L1 Expression in Gastric Cancer Cells |
| 中文关键词 修订日期：2021-10-22 |
| DOI：10.11735/j.issn.1004-0242.2021.12.A009 |
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| 中文关键词: 胃癌 肿瘤免疫 FOXJ2 PD-L1 |
| 英文关键词:gastric cancer immunotherapy FOXJ2 PD-L1 |
| 基金项目:国家重点研发计划（2018YFC1313101）；国家自然科学基金（82073197） |
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| 中文摘要: |
| 摘 要：［目的］ 研究免疫检查点PD-L1在胃癌细胞中的转录调控机制；探讨转录因子FOXJ2对PD-L1的转录调控，两者表达的相关性及其与胃癌患者预后的关系；揭示FOXJ2在调控T细胞抗肿瘤免疫中发挥的生物学功能。［方法］ 利用生物信息学方法筛选能够调控PD-L1的转录因子；免疫组化及免疫荧光检测FOXJ2和PD-L1在胃癌临床标本中的表达以及FOXJ2与CD8+ T细胞浸润的关系；qRT-PCR与Western blot检测FOXJ2和PD-L1在胃癌细胞中的表达；ChIP实验验证FOXJ2与PD-L1基因启动子的直接相互作用；胃癌细胞与T细胞共培养实验检测T细胞对肿瘤细胞的杀伤能力；流式细胞术检测肿瘤细胞中PD-L1表达情况及T细胞中TNF-α和IFN-γ的表达情况。［结果］ JASPAR和PROMO数据库筛选出24个可能调控PD-L1的候选转录因子；癌症公共数据库显示FOXJ2与PD-L1的表达呈正相关（P<0.05），高表达FOXJ2的胃癌患者生存期明显缩短（P<0.01）。FOXJ2在胃癌组织中的表达较癌旁组织显著上调，且与PD-L1的表达呈正相关关系（R=0.629，P<0.01）。qRT-PCR与Western blot证实胃癌细胞中敲低FOXJ2表达后PD-L1表达下降。ChIP实验证实FOXJ2与PD-L1基因启动子区域的直接相互作用。下调胃癌细胞中FOXJ2表达后，T细胞对肿瘤细胞的杀伤能力增强；流式细胞术显示肿瘤细胞中的PD-L1下降，而T细胞中TNF-α和IFN-γ的表达升高。［结论］ FOXJ2与PD-L1表达和胃癌患者的生存密切相关，阻断FOXJ2对PD-L1的转录调控有望成为胃癌免疫治疗的新靶点。 |
| 英文摘要: |
| Abstract：［Purpose］ To investigate the regulatory effect of FOXJ2 on PD-L1 expression in gastric cancer(GC). ［Methods］ Bioinformatics methods were performed to screen transcription factors for regulating PD-L1. The expression of FOXJ2 and PD-L1 in GC specimens was detected by qRT-PCR and Western blot. The relationship between FOXJ2 and CD8+ T cell was explored by immunohistochemistry and immunofluorescence. The ChIP experiments were conducted to verify the interaction between FOXJ2 and PD-L1 promoter. Co-culturing GC cell and T cell were used to detect the killing ability of T cells on tumor cells. Flow cytometry was used to detect the expression of PD-L1 in tumor cells and the expression of TNF-α and IFN-γ in T cells. ［Results］ JASPAR and PROMO databases predicted 24 candidate transcription factors that may regulate PD-L1. The cancer public databases showed that the expression of FOXJ2 and PD-L1 were positively correlated(P<0.05) in GC. The high expression of FOXJ2 correlated with poor GC patient prognosis(P<0.01). The tissue microarrays revealed that the expression of FOXJ2 in GC tissues was higher than that in adjacent tissues， and it was positively correlated with the expression of PD-L1(R=0.629， P<0.01). The expression of PD-L1 decreased if FOXJ2 was downregulated by siRNA in GC cells. ChIP experiments confirmed the direct interaction between FOXJ2 and PD-L1 gene promoter region. When FOXJ2 was downregulated， the killing ability of T cells on tumor cells was enhanced; the expression of PD-L1 decreased in tumor cells， whereas TNF-α and IFN-γ increased in T cells. ［Conclusion］ FOXJ2 is closely related to the survival and prognosis of patients with gastric cancer， and blocking the transcriptional regulation of FOXJ2 on PD-L1 is expected to be a new immunotherapy target in GC. |
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