MUC1-C 是人类癌细胞中 MICA/B NKG2D 配体和外泌体分泌的主调控因子。
MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells.
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Division of Systems Biology, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, Japan.
出版信息
J Immunother Cancer. 2023 Feb;11(2). doi: 10.1136/jitc-2022-006238.
BACKGROUND
The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, MUC1-C promotes oncogenesis in association with chronic inflammation. Aberrant expression of MUC1-C in cancers has been linked to depletion and dysfunction of T cells in the tumor microenvironment. In contrast, there is no known involvement of MUC1-C in the regulation of natural killer (NK) cell function.
METHODS
Targeting MUC1-C genetically and pharmacologically in cancer cells was performed to assess effects on intracellular and cell surface expression of the MHC class I chain-related polypeptide A (MICA) and MICB ligands. The promoters were analyzed for H3K27 and DNA methylation. Shedding of MICA/B was determined by ELISA. MUC1-C interactions with ERp5 and RAB27A were assessed by coimmunoprecipitation and direct binding studies. Exosomes were isolated for analysis of secretion. Purified NK cells were assayed for killing of cancer cell targets.
RESULTS
Our studies demonstrate that MUC1-C represses expression of the MICA and MICB ligands that activate the NK group 2D receptor. We show that the inflammatory MUC1-C→NF-κB pathway drives enhancer of zeste homolog 2-mediated and DNMT-mediated methylation of the and promoter regions. Targeting MUC1-C genetically and pharmacologically with the GO-203 inhibitor induced intracellular and cell surface MICA/B expression but not MICA/B cleavage. Mechanistically, MUC1-C regulates the ERp5 thiol oxidoreductase that is necessary for MICA/B protease digestion and shedding. In addition, MUC1-C interacts with the RAB27A protein, which is required for exosome formation and secretion. As a result, targeting MUC1-C markedly inhibited secretion of exosomes expressing MICA/B. In concert with these results, we show that targeting MUC1-C promotes NK cell-mediated killing.
CONCLUSIONS
These findings uncover pleotropic mechanisms by which MUC1-C confers evasion of cancer cells to NK cell recognition and destruction.
背景
MUC1-C 蛋白在哺乳动物中进化，以保护屏障组织免受动态平衡的丧失；然而，MUC1-C 与慢性炎症一起促进肿瘤发生。癌症中 MUC1-C 的异常表达与肿瘤微环境中 T 细胞的耗竭和功能障碍有关。相比之下，目前还没有已知的 MUC1-C 参与调节自然杀伤 (NK) 细胞功能。
方法
通过基因和药理学靶向癌细胞中的 MUC1-C，评估对 MHC Ⅰ类链相关多肽 A（MICA）和 MICB 配体的细胞内和细胞表面表达的影响。分析启动子的 H3K27 和 DNA 甲基化。通过 ELISA 测定 MICA/B 的脱落。通过共免疫沉淀和直接结合研究评估 MUC1-C 与 ERp5 和 RAB27A 的相互作用。分离外泌体进行分泌分析。纯化 NK 细胞用于测定对癌细胞靶标的杀伤作用。
结果
我们的研究表明，MUC1-C 抑制激活 NK 组 2D 受体的 MICA 和 MICB 配体的表达。我们表明，炎症性 MUC1-C→NF-κB 途径驱动增强子结合蛋白 2 介导和 DNMT 介导的 和 启动子区域的甲基化。用 GO-203 抑制剂基因和药理学靶向 MUC1-C 诱导细胞内和细胞表面 MICA/B 表达，但不诱导 MICA/B 切割。从机制上讲，MUC1-C 调节 ERp5 硫醇氧化还原酶，该酶对于 MICA/B 蛋白酶消化和脱落是必需的。此外，MUC1-C 与 RAB27A 蛋白相互作用，这是外体形成和分泌所必需的。结果，靶向 MUC1-C 显著抑制表达 MICA/B 的外体分泌。与这些结果一致，我们表明靶向 MUC1-C 促进 NK 细胞介导的杀伤。
结论
这些发现揭示了 MUC1-C 赋予癌细胞逃避 NK 细胞识别和破坏的多种机制。
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