RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
c-Myc 靶向 HDAC3 通过组蛋白去乙酰化抑制 N 型 SCLC 中 NKG2DL 表达及先天免疫应答
英文原题：c-Myc Targets HDAC3 to Suppress NKG2DL Expression and Innate Immune Response in N-Type SCLC through Histone Deacetylation.
查看英文原题
c-Myc Targets HDAC3 to Suppress NKG2DL Expression and Innate Immune Response in N-Type SCLC through Histone Deacetylation.
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中文摘要
SCLC 是一种侵袭性恶性肿瘤，预后极差，有效治疗选择有限。尽管肿瘤突变负荷高，但 SCLC 患者对免疫治疗的应答罕见，这可能归因于缺乏免疫监视。
在此，我们旨在研究癌基因 MYC 在调控 NKG2DL 中的作用和机制，NKG2DL 是 SCLC-N 中最相关的 NK 激活配体。
我们对 H2227 细胞、H446 细胞及其他 SCLC 细胞系使用了 Western Blotting、免疫荧光、流式细胞术、定量实时 PCR（qRT-PCR）、共免疫沉淀（Co-IP）、染色质免疫沉淀（ChIP）和细胞毒性试验，发现 c-Myc 负向调控 SCLC-N 细胞中 NKG2DL 的表达。在机制上，c-Myc 招募 HDAC3 使 MICA 和 MICB 启动子区域的 H3K9ac 去乙酰化，抑制 SCLC-N 细胞中 MICA/B 的表达以及 NK 细胞的细胞毒性。使用选择性 HDAC3 抑制剂处理可上调 SCLC-N 细胞上 NKG2DL 的表达，并增强 NK 细胞的细胞毒性。
此外，对 CCLE 和 Kaplan-Meier plotter 数据的分析表明，在 SCLC-N 细胞中 MYC 与 NKG2DL 呈负相关，并且与肺癌患者的预后相关。
总之，这些结果为 c-Myc/HDAC3 轴在 NKG2DL 表达和 SCLC-N 固有免疫逃逸中的作用和机制提供了新的见解，提示其可能是 SCLC-N 免疫治疗的潜在靶点。
展开英文摘要原文
SCLC is an aggressive malignancy with a very poor prognosis and limited effective therapeutic options. Despite the high tumor mutational burden, responses to immunotherapy are rare in SCLC patients, which may be due to the lack of immune surveillance.
Here, we aimed to examine the role and mechanism of oncogene MYC in the regulation of NKG2DL, the most relevant NK-activating ligand in SCLC-N. Western Blotting, Immunofluorescence, flow cytometry, quantitative real-time PCR (qRT-PCR), Co-Immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and Cytotoxicity assay were used on H2227 cells, H446 cells, and other SCLC cell lines, and we found that c-Myc negatively regulated NKG2DL expression in SCLC-N cells.
Mechanistically, c-Myc recruited HDAC3 to deacetylate H3K9ac at the promoter regions of MICA and MICB , suppressing the MICA/B expression of SCLC-N cells and the cytotoxicity of NK cells. Treatment with selective HDAC3 inhibitor up-regulated the expression of NKG2DL on SCLC-N cells and increased the cytotoxicity of NK cells.
Furthermore, analysis of the CCLE and Kaplan-Meier plotter data performed the negative correlation between MYC and NKG2DL in SCLC-N cells and the correlation with the prognosis of lung cancer patients. Collectively, the results provided the new insight into the role and mechanism of c-Myc/HDAC3 axis in NKG2DL expression and innate immune escape of SCLC-N, suggesting the potential target for SCLC-N immunotherapy.
论文信息
- 作者
- Zhao P、Sun X、Li H、Liu Y、Cui Y、Tian L、Cheng Y
- 第一作者单位
- Postdoctoral Research Workstation, Jilin Cancer Hospital, Changchun 130012, China.China
- 通讯作者单位
- Medical Oncology Translational Research Lab, Jilin Cancer Hospital, Changchun 130012, China.China
- 期刊
- Cancers2022 Jan 18
- 原文标识
- PubMed 35158730 · DOI 10.3390/cancers14030457
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