Exosomal lncRNA NEAT1 Inhibits NK-Cell Activity to Promote Multiple Myeloma Cell Immune Escape via an EZH2/PBX1 Axis.

IF 4.1 2区医学 Q2 CELL BIOLOGY Molecular Cancer Research Pub Date : 2024-02-01 DOI:10.1158/1541-7786.MCR-23-0282

Qing-Ming Wang, Guang-Yu Lian, Su-Mei Sheng, Jing Xu, Long-Long Ye, Chao Min, Shu-Fang Guo

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Abstract

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

来源于癌症细胞的外显体长非编码RNA（lncRNA）参与各种过程，包括癌症细胞增殖、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）细胞免疫逃逸中的作用和潜在机制。获得MM患者的MM细胞和样本。利用EdU染色、CCK-8、流式细胞术和ELISA评估MM细胞来源的外泌体（MM外泌体）和外泌体NEAT1对NK细胞功能的影响。染色质和RNA免疫沉淀用于鉴定NEAT1、Zeste同源物2的增强子（EZH2）和前B细胞白血病转录因子1（PBX1）之间的相互作用。构建异种移植物肿瘤模型以验证外泌体NEAT1对肿瘤生长的影响。用qRT-PCR、westernblot和免疫组织化学方法检测相关基因。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沉默的外泌体几乎没有作用。NEAT1通过招募EZH2使PBX1沉默。PBX1敲除消除了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的肿瘤生长，降低Ki67和PD-L1，并增加肿瘤组织中的NKG2D、TNF-α和IFN-γ。总之，MM细胞衍生的外泌体NEAT1通过下调PBX1抑制NK细胞活性，促进MM细胞免疫逃逸。本研究提出了一种治疗MM的潜在策略。提示：本研究揭示了外泌体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，为MM的治疗提供了新的潜力。

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来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.