Exosomal MiR-4261 mediates calcium overload in RBCs by downregulating the expression of ATP2B4 in multiple myeloma

Abstract

BackgroundHypercalcemia 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.MethodsA 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 Ca2+-ATPase 4 (PMCA4) in RBCs.ResultsThe 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.ConclusionsStudies 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.

Utilizing 3D Models to Unravel the Dynamics of Myeloma Plasma Cells’ Escape from the Bone Marrow Microenvironment

“…These studies demonstrate the ability of microfluidic chips to precisely control individual cells in flow, which, coupled with recent developments in next-generation sequencing, provides novel opportunities to identify new pathways and markers governing cell fate. Performing simultaneous genome and transcriptome profiling on these circulating tumour cells has been shown to be feasible and highly prognostic, confirming the validity of this approach [ 84 , 86 ].…”

Recent advancements of miRNAs in the treatment of bone diseases and their delivery potential

“…miRNA-29b has been projected as a tumor suppressor in multiple myeloma as it was shown to induce apoptosis in human myeloma cell lines and is antagonistic with IL-6 ( Zhang et al., 2011 ). Exosomal miR-4261 can target and downregulate the ATP2B4 of the red blood cells with hypercalcemia, suggesting it to be an efficient therapeutic agent ( Bian et al., 2022 ). The encapsulation of miR-34a into chitosan/PLGA nanoparticles can be employed as a potential therapeutic against multiple myeloma disease as it hindered the tumor growth in mice models ( Cosco et al., 2015 ).…”