Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210001, P. R. China.
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, P. R. China.
Cancer Commun (Lond). 2022 Nov;42(11):1185-1206. doi: 10.1002/cac2.12356. Epub 2022 Aug 30.
Multiple myeloma (MM) is the second most common hematological malignancy. An overwhelming majority of patients with MM progress to serious osteolytic bone disease. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) participates in several steps during cancer development and osteoclast differentiation. This study aimed to explore its role in MM.
The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis. Enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotting were used to detect AIMP1 expression. Protein chip analysis, RNA-sequencing, and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1. The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in vitro and a xenograft model in vivo. Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro. A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.
AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes. Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A) to regulate histone H3 acetylation. In addition, AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2 (GAREM2) to increase the phosphorylation of extracellular-regulated kinase 1/2 (p-ERK1/2). Furthermore, AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1 (NFATc1) in vitro. In contrast, exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.
Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM, which accelerates MM malignancy via activation of the MAPK signaling pathway.
多发性骨髓瘤（MM）是第二大常见的血液系统恶性肿瘤。绝大多数 MM 患者进展为严重的溶骨性骨病。氨酰-tRNA 合成酶相互作用多功能蛋白 1（AIMP1）参与癌症发展和破骨细胞分化的多个步骤。本研究旨在探讨其在 MM 中的作用。
应用 MM 的基因表达谱队列确定 AIMP1 的表达及其与 MM 患者预后的关系。酶联免疫吸附试验、免疫组织化学和 Western blot 用于检测 AIMP1 的表达。蛋白质芯片分析、RNA-seq、染色质免疫沉淀和下一代测序用于筛选 AIMP1 的相互作用蛋白和关键下游靶标。体外 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）测定和体内异种移植模型确定 AIMP1 对细胞增殖的影响。体外通过抗酒石酸酸性磷酸酶染色评估骨病变。使用 NOD/SCID-TIBIA 小鼠模型评估载有 siAIMP1 的外泌体对体内骨病变形成的影响。
AIMP1 在 MM 患者中的表达增加，与不良预后密切相关。AIMP1 表达增加通过激活丝裂原活化蛋白激酶（MAPK）信号通路促进 MM 细胞在体外和体内的增殖。蛋白质芯片检测和后续实验表明，AIMP1 与酸性亮氨酸丰富核磷蛋白 32 家族成员 A（ANP32A）相互作用，调节组蛋白 H3 乙酰化。此外，AIMP1 增加 GRB2 相关和 MAPK 蛋白 2（GAREM2）的组蛋白 H3 乙酰化富集功能，增加细胞外调节激酶 1/2（p-ERK1/2）的磷酸化。此外，AIMP1 通过体外激活核因子活化 T 细胞 c1（NFATc1）促进破骨细胞分化。相反，外泌体包裹的 AIMP1 小干扰 RNA 有效抑制了体外和体内 MM 的进展和破骨细胞分化。
我们的数据表明，AIMP1 是 MM 中组蛋白 H3 乙酰化的新型调节因子，通过激活 MAPK 信号通路加速 MM 的恶性程度。
