A novel circRNA-miRNA-mRNA network revealed exosomal circ-ATP10A as a biomarker for multiple myeloma angiogenesis

Abstract

The importance of angiogenesis in multiple myeloma (MM) is unquestionable; however, to date, the success of antiangiogenic therapies has been fairly limited. Exosomal circular RNAs (circRNAs) have been proven to be pivotal players in angiogenesis in various cancers. Nevertheless, their role in MM remains unknown. Therefore, we aimed to identify differentially expressed circRNAs in peripheral blood exosomes from MM patients and explore their diagnostic and prognostic values. We screened 2,052 circRNAs with significant differential expression between MM patients and healthy controls via high-throughput sequencing. qRT-PCR confirmed that the expression of circ-ATP10A was significantly increased in MM patients. The bioinformatics analyses suggested that circ-ATP10A can act as a microRNA (miRNA) sponge and regulate the expression of downstream vascular endothelial growth factor-B (VEGFB), hypoxia-inducible factor-1alpha (HIF1A), platelet-derived growth factor subunit A (PDGFA), and fibroblast growth factor (FGF). The immunohistochemical results indicated that the circ-ATP10A level was positively correlated with the protein levels of VEGFB and marrow microvessel density (MVD) in MM patients, and the receiver operating characteristic (ROC) curve, area under the ROC curve (AUC) and Kaplan-Meier survival curve analyses confirmed it as a prognostic biomarker. Collectively, our study indicates that exosomal circ-ATP10A is a valuable prognostic biomarker in MM and may promote MM angiogenesis by targeting hsa-miR-6758-3p/hsa-miR-3977/hsa-miR-6804-3p/hsa-miR-1266-3p/hsa-miR-3620-3p and modulating their downstream mRNAs, such as VEGFB, HIF1A, PDGF, and FGF.

Review of the Role of Mesenchymal Stem Cells and Exosomes Derived from Mesenchymal Stem Cells in the Treatment of Orthopedic Disease

“…The expression of circ-ATP10A in patients with MM is significantly increased. Bioinformatics studies have found that circRNA-ATP10A can act as the sponge of hsa-miR-6758-3p/hsa-miR3977/hsa-miR-6804-3p/hsa-miR 1266-3p/hsa-miR-3620-3p and regulate downstream mRNA, thus upregulating the expression of VEGF-B, HIF-1α, platelet-derived growth factor A, and fibroblast growth factor to achieve angiogenesis in MM [ 67 ]. MM-Exos activate the EGF pathway in the bone microenvironment through rich double regulatory protein (amphiregulin, AREG), which leads to osteoclast formation.…”

Circular RNA as a Novel Biomarker for Diagnosis and Prognosis and Potential Therapeutic Targets in Multiple Myeloma

“…An experiment recognized a difference in the expression of circRNAs in exosomes from the blood of MM subjects for evaluating prognostic significance. These findings established that the levels of circ-ATP10A were remarkably increased in MM subjects [ 77 ]. The bioinformatics assessment indicated that circ-ATP10A can operate as a miRNA sponge and controls the concentrations of several growth factors, such as hypoxia-inducible factor-1alpha (HIF1A), platelet-derived growth factor subunit A (PDGFA), VEGFB, and fibroblast growth factor (FGF), while the circ-ATP10A concentration was correlated with BM microvessel density.…”

“…The bioinformatics assessment indicated that circ-ATP10A can operate as a miRNA sponge and controls the concentrations of several growth factors, such as hypoxia-inducible factor-1alpha (HIF1A), platelet-derived growth factor subunit A (PDGFA), VEGFB, and fibroblast growth factor (FGF), while the circ-ATP10A concentration was correlated with BM microvessel density. These effects were obtained by targeting miRNA-6758-3p/miRNA-3977/miRNA-6804-3p/miRNA-1266-3p/miRNA-3620-3p [ 77 ] ( Table 1 , Figure 3 ).…”

Exosomes in multiple myeloma: from bench to bedside

“…Similarly, exosomal circG042080 was identified as a possible predictor for MM-related myocardial damage 105 . Moreover, a recent paper found that exosomal circATP10A in MM patients had prognostic potential and correlated to VEGFB protein levels, suggesting involvement in angiogenesis 106 .…”