肿瘤细胞治疗研究
英文原题：Exosomal lncRNA NEAT1 Inhibits NK-Cell Activity to Promote Multiple Myeloma Cell Immune Escape via an EZH2/PBX1 Axis.
多发性骨髓瘤细胞来源的外泌体NEAT1通过下调PBX1抑制NK细胞活性，促进多发性骨髓瘤细胞免疫逃逸。
外泌体长链非编码RNA（lncRNA）来源于癌细胞，参与多种过程，包括癌细胞增殖、转移和免疫调节。我们研究了外泌体传递的lncRNA NEAT1在多发性骨髓瘤细胞逃逸自然杀伤（NK）细胞免疫中的作用及其潜在机制。获取多发性骨髓瘤细胞和多发性骨髓瘤患者样本。使用EdU染色、CCK-8、流式细胞术和ELISA评估多发性骨髓瘤细胞来源外泌体（多发性骨髓瘤外泌体）及外泌体NEAT1对NK细胞功能的影响。进行染色质和RNA免疫沉淀以鉴定NEAT1、zeste同源增强子2（EZH2）和前B细胞白血病转录因子1（PBX1）之间的相互作用。构建异种移植肿瘤模型以验证外泌体NEAT1对肿瘤生长的影响。进行qRT-PCR、Western blot分析和IHC以检测相关基因。NEAT1水平在多发性骨髓瘤肿瘤组织、多发性骨髓瘤细胞和多发性骨髓瘤外泌体中上调。多发性骨髓瘤外泌体抑制细胞增殖，促进凋亡，减少自然杀伤组2成员D（NKG2D）阳性细胞以及NK细胞中TNFα和干扰素-γ（IFN-γ）的产生，而NEAT1沉默的外泌体几乎没有影响。NEAT1通过招募EZH2沉默PBX1。PBX1敲低消除了NEAT1沉默外泌体对NK和多发性骨髓瘤细胞的影响。NEAT1沉默的外泌体抑制小鼠肿瘤生长，降低Ki67和PD-L1，并增加肿瘤组织中的NKG2D、TNFα和IFNγ。总之，多发性骨髓瘤细胞来源的外泌体NEAT1通过下调PBX1抑制NK细胞活性，促进多发性骨髓瘤细胞免疫逃逸。本研究为多发性骨髓瘤的治疗提示了一种潜在策略。意义：本研究揭示外泌体NEAT1调控EZH2/PBX1轴抑制NK细胞活性，从而促进多发性骨髓瘤细胞免疫逃逸，为多发性骨髓瘤提供了新的治疗潜力。
UNLABELLED: Exosomal long noncoding RNAs (lncRNA) derived from cancer cells are implicated in various processes, including cancer cell proliferation, metastasis, and immunomodulation. We investigated the role and underlying mechanism of exosome-transmitted lncRNA NEAT1 in the immune escape of multiple myeloma cells from natural killer (NK) cells. Multiple myeloma cells and samples from patients with multiple myeloma were obtained. The effects of multiple myeloma cell-derived exosomes (multiple myeloma exosomes) and exosomal NEAT1 on the functions of NK cells were evaluated using EdU staining, CCK-8, flow cytometry, and ELISA. Chromatin and RNA immunoprecipitation were performed to identify interactions between NEAT1, enhancer of Zeste Homolog 2 (EZH2), and pre-B-cell leukemia transcription factor 1 (PBX1). A xenograft tumor model was constructed to verify the effects of exosomal NEAT1 on tumor growth. qRT-PCR, Western blot analysis, and IHC were conducted to detect related genes. NEAT1 levels were upregulated in multiple myeloma tumor tissues, multiple myeloma cells, and multiple myeloma exosomes. Multiple myeloma exosomes suppressed cell proliferation, promoted apoptosis, reduced natural killer group 2, member D (NKG2D)-positive cells, and the production of TNFα) and interferon-gamma (IFN-γ) in NK cells, whereas NEAT1-silenced exosomes had little effect. NEAT1 silenced PBX1 by recruiting EZH2. PBX1 knockdown abrogated the effects of NEAT1-silenced exosomes on NK and multiple myeloma cells. NEAT1-silenced exosomes inhibited tumor growth in mice, decreased Ki67 and PD-L1, and increased NKG2D, TNFα, and IFNγ in tumor tissues. In summary, multiple myeloma cell-derived exosomal NEAT1 suppressed NK-cell activity by downregulating PBX1, promoting multiple myeloma cell immune escape. This study suggests a potential strategy for treating multiple myeloma. IMPLICATIONS: This study reveals that exosomal NEAT1 regulates EZH2/PBX1 axis to inhibit NK-cell activity, thereby promoting multiple myeloma cell immune escape, which offers a novel therapeutic potential for multiple myeloma.
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