Exosomal long noncoding RNAs (lncRNAs) 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 (MM) cells from natural killer (NK) cells. MM cells and samples from MM patients were obtained. The effects of MM cell-derived exosomes (MM 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 and immunohistochemistry were conducted to detect related genes. NEAT1 levels were upregulated in MM tumor tissues, MM cells, and MM exosomes. MM exosomes suppressed cell proliferation, promoted apoptosis, reduced natural killer group 2, member D (NKG2D)-positive cells, and the production of tumor necrosis factor alpha (TNF-α) 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 MM cells. NEAT1-silenced exosomes inhibited tumor growth in mice, decreased Ki67 and PD-L1, and increased NKG2D, TNF-α, and IFN-γ in tumor tissues. In summary, MM cell-derived exosomal NEAT1 suppressed NK cell activity by downregulating PBX1, promoting MM cell immune escape. This study suggests a potential strategy for treating MM. 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 MM.

中文翻译：

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外泌体lncRNA NEAT1抑制NK细胞活性，通过EZH2/PBX1轴促进多发性骨髓瘤细胞免疫逃逸

源自癌细胞的外泌体长非编码 RNA (lncRNA) 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输的 lncRNA NEAT1 在多发性骨髓瘤 (MM) 细胞从自然杀伤 (NK) 细胞中免疫逃逸中的作用和潜在机制。获得 MM 细胞和来自 MM 患者的样本。使用EdU染色、CCK-8、流式细胞术和ELISA评估MM细胞源性外泌体（MM外泌体）和外泌体NEAT1对NK细胞功能的影响。通过染色质和 RNA 免疫沉淀来鉴定 NEAT1、Zeste 同源物 2 (EZH2) 增强子和前 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来验证外泌体NEAT1对肿瘤生长的影响。采用qRT-PCR、western blot和免疫组化检测相关基因。NEAT1 水平在 MM 肿瘤组织、MM 细胞和 MM 外泌体中上调。MM外泌体抑制细胞增殖，促进细胞凋亡，减少自然杀伤组2、成员D（NKG2D）阳性细胞，以及NK细胞中肿瘤坏死因子α（TNF-α）和干扰素-γ（IFN-γ）的产生，而 NEAT1 沉默的外泌体则几乎没有影响。NEAT1 通过招募 EZH2 来沉默 PBX1。PBX1 敲低消除了 NEAT1 沉默的外泌体对 NK 和 MM 细胞的影响。NEAT1 沉默的外泌体抑制小鼠肿瘤生长，降低肿瘤组织中的 Ki67 和 PD-L1，并增加 NKG2D、TNF-α 和 IFN-γ。总之，MM细胞来源的外泌体NEAT1通过下调PBX1抑制NK细胞活性，促进MM细胞免疫逃逸。这项研究提出了治疗 MM 的潜在策略。意义：本研究揭示外泌体 NEAT1 调节 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，这为 MM 提供了新的治疗潜力。