| 张小燕,尚红梅,汪丹丹,陈 芳,王海燕,郭晨明.SOX2影响PD-L1表达参与乳腺癌细胞免疫逃逸的机制探讨[J].,2024,(9):1628-1632 |
| SOX2影响PD-L1表达参与乳腺癌细胞免疫逃逸的机制探讨 |
| Mechanism of SOX2 Induced PD-L1 Expression Promoting Immune Escape of Breast Cancer Cells |
| 投稿时间：2023-10-31 修订日期：2023-11-23 |
| DOI：10.13241/j.cnki.pmb.2024.09.005 |
| 中文关键词: 乳腺癌 免疫逃逸 转录因子性别决定区Y框蛋白2 程序性死亡因子配体1 |
| 英文关键词: Breast cancer Immune escape Transcription factor sex determining region Y box protein 2 Programmed death factor ligand 1 |
| 基金项目:新疆维吾尔自治区自然科学基金项目（2022D01A140） |
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| 中文摘要: |
| 摘要 目的：探讨转录因子性别决定区Y框蛋白2（SOX2）基因通过诱导程序性死亡因子配体1（PD-L1）表达，促进乳腺癌细胞免疫逃逸的作用机制。方法：qRT-PCR和Western blot法检测人乳腺癌细胞系MDA-MB-231、SK-BR-3和正常乳腺上皮细胞系MCF10A中SOX2、PD-L1、T细胞免疫球蛋白及粘蛋白结构域分子3（TIM3）和核受体亚家族4 A组成员1（NR4A1）的mRNA表达量及对应蛋白表达量。分别构建SOX2敲减质粒NC和si-SOX2并转染MDA-MB-231，与细胞因子诱导的杀伤细胞构建共培养体系，连续培养48h，MTT法检测细胞增殖率，TUNEL法检测细胞凋亡率，乳酸脱氢酶（LDH）释放实验检测 T细胞杀伤率，ELISA检测T细胞活化标志物IL-2和IFN-γ，qRT-PCR 检测 T 细胞耗竭标志物 PD-1、TIM3和NR4A1 mRNA表达量。结果：与MCF10A相比，MDA-MB-231与SK-BR-3中SOX2、PD-L1、TIM3、NR4A1的mRNA表达量及对应蛋白表达量均显著升高（P＜0.05）。与空白组和NC组相比，si-SOX2组SOX2 mRNA和PD-L1蛋白表达量明显下降，细胞增殖率显著下降，细胞凋亡率增加，T细胞杀伤率增加，IL-2和IFN-γ水平升高，PD-1、TIM3和NR4A1 mRNA表达量降低（P＜0.05）。结论：SOX2基因可能通过诱导PD-L1高表达，进而促使乳腺癌细胞免疫逃逸的能力增强，沉默SOX2表达可以增强T细胞杀伤力，抑制肿瘤增殖，SOX2基因有望成为乳腺癌干预的重要分子靶点。 |
| 英文摘要: |
| ABSTRACT Objective: To investigate the mechanism of transcription factor sex determining region Y box protein 2 (SOX2) gene promoting immune escape of breast cancer cells by inducing the expression of programmed death factor ligand 1 (PD-L1). Methods: The expressions of SOX2, PD-L1, T cell immunoglobulin and mucin domain molecule 3 (TIM3), and nuclear receptor subfamily 4A group member 1 (NR4A1) mRNA and corresponding protein expressions in human breast cancer cell lines MDA-MB-231, SK-BR-3 and normal breast epithelial cell line MCF10A were detected by qRT-PCR, and Western blot. SOX2 knockdown plasmids NC and si-SOX2 were constructed, transfected with MDA-MB-231, and constructed a coculture system with cytokine induced killer cells. They were continuously cultured for 48 hours, cell proliferation rate was detected by MTT assay, apoptosis rate was detected by TUNEL assay, T cell killing rate was detected by lactate dehydrogenase (LDH) release assay, T cell activation markers IL-2 and IFN-γ were detected by ELISA, the mRNA expression levels of T cell depletion marker PD-1, TIM3, and NR4A1 were detected by qRT-PCR. Results: Compared with MCF10A, the expression levels of SOX2, PD-L1, TIM3, NR4A1 mRNA and corresponding protein expressions in MDA-MB-231 and SK-BR-3 were significantly increased (P<0.05). Compared with the blank group and NC group, the si-SOX2 group showed significant decrease in the expressions of SOX2 mRNA and PD-L1 protein, significant decrease in cell proliferation rate, increase in cell apoptosis rate, increase in T cell killing rate, increase in IL-2 and IFN-γ levels, decrease in the mRNA expression levels of PD-1, TIM3, and NR4A1 (P<0.05). Conclusion: SOX2 gene may enhance the immune escape ability of breast cancer cells by inducing high expression of PD-L1. Silencing SOX2 expression can enhance the lethality of T cells and inhibit tumor proliferation. SOX2 gene is expected to become an important molecular target of breast cancer intervention. |
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