miRNA-98-5p Targeting IGF2BP1 Induces Mesenchymal Stem Cell Apoptosis by Modulating PI3K/Akt and p53 in Immune Thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is a common hematological autoimmune disease, in which defective mesenchymal stem cells (MSCs) are potentially involved. Our previous study suggested that MSCs in ITP patients displayed enhanced apoptosis. MicroRNAs (miRNAs) play important roles in ITP by affecting megakaryopoiesis, platelet production and immunoregulation, whereas the roles of miRNAs in ITP-MSCs remain unknown. In a previous study, we performed microarray analysis to obtain mRNA and miRNA profiles of ITP-MSCs. In the present study, we reanalyze the data and identify miR-98-5p as a candidate miRNA contributing to MSC deficiency in ITP. miR-98-5p acts through targeting insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and the subsequent downregulation of insulin-like growth factor 2 (IGF-2) causes inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in the process of MSC deficiency. Furthermore, miR-98-5p upregulates p53 by inhibiting b-transducin repeat-containing protein (b-TrCP)dependent p53 ubiquitination. Moreover, miR-98-5p overexpression impairs the therapeutic effect of MSCs in ITP mice. All-trans retinoic acid (ATRA) protects MSCs from apoptosis by downregulating miR-98-5p, thus providing a potential therapeutic approach for ITP. Our findings demonstrate that miR-98-5p is a critical regulator of ITP-MSCs, which will help us thoroughly understand the pathogenesis of ITP.

miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway

“…Abnormal expression of miRNAs has been documented to be associated with inflammation and tumor progression. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 miR-4721 was first identified in 2011, 11 yet knowledge about the regulatory function and its role in carcinogenesis is still lacking.…”

iTRAQ‐based quantitative proteomics analysis of immune thrombocytopenia patients before and after Qishunbaolier treatment

“…The above‐mentioned results imply that MIF, IGHM, and PGK1 may affect the function of platelets which are highly related to ITP. Overexpression of the miR‐98‐5p can inhibit the PI3K/Akt signaling pathway and impair the therapeutic effect of MSCs in ITP mice 42 . Furthermore, the PPAR and NF‐κB signaling pathways are involved in regulating ITPs 43 .…”

“…Overexpression of the miR-98-5p can inhibit the PI3K/Akt signaling pathway and impair the therapeutic effect of MSCs in ITP mice. 42 Furthermore, the PPAR and NF-κB signaling pathways are involved in regulating ITPs. 43 The PI3K/Akt, PPAR, and NF-κB signaling pathways related to ITP are also those that are highly enriched by the 20 differentially expressed proteins described here (Figure 3).…”

Gene mutations in the PI3K/Akt signaling pathway were related to immune thrombocytopenia pathogenesis

“…Wang et al through enhanced autophagy-related protein and autophagy ux in PI3K/Akt/mTOR signaling pathway, inhibiting apoptosis and improving platelet viability, thereby alleviating platelet destruction and prolonging the life span of platelets from ITP patients [12]. Furthermore, microRNAs acts through targeting insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and the subsequent downregulation of insulin-like growth factor 2 (IGF-2) causes inhibition of the PI3K/Akt pathway, which is involved in the process of MSC(mesenchymal stem cells de ciency) in ITP [39].We reported previously that abnormal expression of multiple proteins in PI3K/Akt pathway in patient groups compared with control groups using protein pro les technology [18]. In support of this nding, this study con rmed some exon mutations (PTEN, INSR, COCH, MAMDC4, FAAP20 and MUC20) in PI3K/Akt pathway at the gene level in ITP bone marrow samples, which further veri ed the important role of this signaling pathway in ITP pathogenesis.…”