HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma.
HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma.
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HNRNPA2B1介导的TLR4 mRNA m6A修饰促进多发性骨髓瘤的进展
DOI：
10.1186/s12967-022-03750-8
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发表时间：
2022-11-18
影响因子：
7.4
通讯作者：
Zhang, Yu
中科院分区：
文献类型：
--
作者：
Quan, Lina;Jia, Chuiming;Guo, Yiwei;Chen, Yao;Wang, Xinya;Xu, Qiuting;Zhang, Yu
多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，目前仍无法治愈。Toll样受体4（TLR 4）作为一种应激反应信号，在蛋白酶体抑制剂（PI）暴露过程中保护线粒体，维持线粒体代谢，增加MM的耐药性。本研究旨在探讨多发性骨髓瘤的甲基化模式及其对HNRNPA 2B 1及其下游靶基因表达的影响。采用比色法检测MM和正常骨髓标本的甲基化水平。通过腺病毒转染在RPMI 8226 MM细胞中实现HNRNPA 2B 1基因敲低。CCK 8法检测细胞增殖，流式细胞术检测细胞凋亡。应用转录组测序和m6 A甲基化MeRIP测序，检测差异表达基因（DEG）。应用三个独立的NCBI GEO数据集来检查HNRNPA 2B 1和TLR 4表达对MM患者存活的影响。HNRNPA 2B 1促进MM进展。数据库的临床数据显示，HNRNPA 2B 1是MM患者生存的不良预后因素。此外，转录组测序和甲基化测序显示，HNRNPA 2B 1识别并富集在TLR 4的m6 A位点，并且TLR 4在HNRNPA 2B 1敲低的MM细胞中下调m6 A水平和转录水平。此外，TLR 4是基于数据库分析的不利生存预后因素。总体而言，我们的研究表明，RNA结合蛋白HNRNPA 2B 1通过TLR 4信号转导增加MM中的细胞增殖并解除细胞凋亡。我们的研究表明HNRNPA 2B 1是MM的潜在治疗靶点。在线版本包含补充材料，可在10.1186/s12967-022-03750-8获得。
Multiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Toll-like receptor 4 (TLR4) acts as a stress-responsive signal, protecting mitochondria during proteasome inhibitor (PI) exposure, maintaining mitochondrial metabolism and increasing drug resistance in MM. However, the mechanism of TLR4 regulation remains elusive. The purpose of this study was to investigate the methylation pattern of multiple myeloma and its effect on the expression of HNRNPA2B1 and downstream targets. The methylation level in MM and normal bone marrow specimens was detected using a colorimetric assay. HNRNPA2B1 gene knockdown was achieved in RPMI 8226 MM cells via adenovirus transfection. CCK8 and flow cytometric assays were used to detect proliferation and apoptosis, respectively. Transcriptome sequencing and m6A methylation MeRIP sequencing were applied, and differentially expressed genes (DEGs) were detected. Three independent NCBI GEO datasets were applied to examine the effects of HNRNPA2B1 and TLR4 expression on MM patient survival. HNRNPA2B1 promoted MM progression. Clinical data from database revealed that HNRNPA2B1 was adverse prognostic factor for survival among MM patients. Furthermore, transcriptome sequencing and methylation sequencing showed that HNRNPA2B1 recognized and was enriched at the m6A sites of TLR4 and TLR4 was down-regulated of both the m6A level and transcription level in HNRNPA2B1-knockdown MM cells. Moreover, TLR4 was an adverse survival prognostic factor based on database analysis. Overall, our study implies that the RNA-binding protein HNRNPA2B1 increases cell proliferation and deregulates cell apoptosis in MM through TLR4 signaling. Our study suggests HNRNPA2B1 as a potential therapeutic target for MM. The online version contains supplementary material available at 10.1186/s12967-022-03750-8.
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