N6-methyladenosine-induced miR-182-5p promotes multiple myeloma tumorigenesis by regulating CAMK2N1.

IF 3.5 2区 生物学 Q3 CELL BIOLOGY Molecular and Cellular Biochemistry Pub Date : 2024-11-01 Epub Date: 2024-01-05 DOI:10.1007/s11010-023-04906-w
Jing Bao, Tingting Xu, Wanjie Wang, Han Xu, Xiaowen Chen, Ruixiang Xia
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Abstract

Methyltransferase like 3 (METTL3) has been reported to promote tumorigenesis of multiple myeloma (MM), however, the molecular mechanism still needs further research. The N6-methyladenosine (m6A) level in tissues or cells was measured by m6A kit and dot blot assay. The mRNA and protein expression were detected by quantitative real-time PCR (RT-qPCR) and Western blot, respectively. The cell counting kit-8 and colony formation assay were used to detect the cell proliferation. Coimmunoprecipitation (Co-IP) experiment verified the binding of two proteins. The luciferase reporter experiment demonstrated the targeted binding of miR-182-5p and CaMKII inhibitor 1 (CAMK2N1). More importantly, tumor growth was measured in xenograft mice. Our data showed that the expression of METTL3 was significantly increased in MM patients' samples and MM cells. METTL3 overexpression promoted MM cells proliferation, and METTL3 knockdown inhibited MM cells proliferation. Mechanically, METTL3-dependent m6A participated in DiGeorge syndrome critical region 8 (DGCR8)-mediated maturation of pri-miR-182. Upregulation of miR-182-5p further enhanced the promoting proliferation effect of METTL3 overexpression on MM cells. Moreover, the luciferase reporter gene experiment proved that miR-182-5p targetedly regulated CAMK2N1 expression. Xenograft tumor in nude mice further verified that METTL3 promoted MM tumor growth through miR-182/CAMK2N1 signal axis. In summary, the METTL3/miR-182-5p/CAMK2N1 axis plays an important role in MM tumorigenesis, which may provide a new target for MM therapy.

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N6-甲基腺苷诱导的miR-182-5p通过调节CAMK2N1促进多发性骨髓瘤肿瘤发生
据报道,类甲基转移酶3(METTL3)可促进多发性骨髓瘤(MM)的肿瘤发生,但其分子机制仍有待进一步研究。组织或细胞中的 N6-甲基腺苷(m6A)水平通过 m6A 试剂盒和点印迹法测定。mRNA 和蛋白表达分别通过实时定量 PCR(RT-qPCR)和 Western 印迹进行检测。细胞计数试剂盒-8 和菌落形成检测法用于检测细胞增殖。共免疫沉淀(Co-IP)实验验证了两种蛋白的结合。荧光素酶报告实验证明了 miR-182-5p 和 CaMKII 抑制剂 1(CAMK2N1)的靶向结合。更重要的是,在异种移植小鼠中测量了肿瘤的生长情况。我们的数据显示,在 MM 患者样本和 MM 细胞中,METTL3 的表达明显增加。METTL3的过表达促进了MM细胞的增殖,而METTL3的敲除抑制了MM细胞的增殖。从机制上讲,METTL3依赖的m6A参与了迪乔治综合征临界区8(DGCR8)介导的pri-miR-182的成熟。miR-182-5p的上调进一步增强了METTL3过表达对MM细胞的增殖促进作用。此外,荧光素酶报告基因实验证明,miR-182-5p 能靶向调控 CAMK2N1 的表达。裸鼠移植肿瘤进一步验证了METTL3通过miR-182/CAMK2N1信号轴促进MM肿瘤生长。综上所述,METTL3/miR-182-5p/CAMK2N1轴在MM肿瘤发生中起着重要作用,这可能为MM治疗提供了一个新靶点。
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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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