外泌体 miR-4261 通过下调多发性骨髓瘤中 ATP2B4 的表达介导红细胞钙超载。
Exosomal MiR-4261 mediates calcium overload in RBCs by downregulating the expression of ATP2B4 in multiple myeloma.
作者信息
Bian Sicheng, Zhang Xialin, Lin Leilei, Sun Lili, Guo Zhibo, Pan Jie, Cui Jiangxia, Yao Hanbing, Xu Jing, Hao Zhuanghui, Wang Yuzhu, Tong Liguo, Bu Xingpeng, Kong Desheng, Liu Nianjiao, Li Yinghua
机构信息
Key Laboratory of Cell Transplantation of National Health Commission, Heilongjiang Key Laboratory of Blood and Hematopoietic System, Harbin Medical University, Harbin, China.
Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
出版信息
Front Oncol. 2022 Aug 26;12:978755. doi: 10.3389/fonc.2022.978755. eCollection 2022.
BACKGROUND
Hypercalcemia induced by multiple myeloma (MM) affects the biological functions of excitable and non-excitable cells. However, red blood cells (RBCs) regulatory effect on calcium in hypercalcemia is still not fully understood.
METHODS
A total of 113 patients with MM osteolytic lesions were studied retrospectively. Flow cytometry and atomic absorption spectroscopy were used to detect calcium content. Immunofluorescence and Western blotting were used to investigate protein expression. GEO and miRNA databases were used to screen miRNAs. Exosomal miR-4261 migration was investigated by Transwell assay. Dual-luciferase assays confirmed the targeting relationship between miR-4261 and ATP2B4. An RBC oxidative stress model was constructed, and Omega-Agatoxin IVA was used to study the role of plasma membrane Ca-ATPase 4 (PMCA4) in RBCs.
RESULTS
The results showed that MM RBCs had calcium overload, and serum calcium levels increased as the number of RBCs decreased. The expression of PMCA4 in MM RBCs was significantly lower than in normal RBCs. The exosomal miR-4261 produced by MM cells could be transferred to RBCs to downregulate the expression of ATP2B4.
CONCLUSIONS
Studies have confirmed that RBCs experience calcium overload in MM with osteolytic lesions, which is related to the downregulation of ATP2B4 by MM exosomal miR-4261.
背景
多发性骨髓瘤（MM）所致高钙血症会影响可兴奋细胞和非可兴奋细胞的生物学功能。然而，红细胞（RBC）在高钙血症中对钙的调节作用仍未完全明确。
方法
回顾性研究113例伴有溶骨性病变的MM患者。采用流式细胞术和原子吸收光谱法检测钙含量。运用免疫荧光和蛋白质印迹法研究蛋白质表达。利用GEO和miRNA数据库筛选miRNA。通过Transwell实验研究外泌体miR - 4261的迁移。双荧光素酶实验证实miR - 4261与ATP2B4之间的靶向关系。构建红细胞氧化应激模型，并使用ω - 银环蛇毒素IVA研究质膜钙ATP酶4（PMCA4）在红细胞中的作用。
结果
结果显示，MM患者的红细胞存在钙超载，且血清钙水平随红细胞数量减少而升高。MM患者红细胞中PMCA4的表达显著低于正常红细胞。MM细胞产生的外泌体miR - 4261可转移至红细胞，下调ATP2B4的表达。
结论
研究证实，伴有溶骨性病变的MM患者红细胞存在钙超载，这与MM外泌体miR - 4261下调ATP2B4有关。
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