Downregulation of MicroRNA-93 inhibits proliferation and promotes apoptosis and hematopoiesis in myelodysplastic syndrome cells through PAG1-mediated epidermal growth factor receptor signaling pathway.

Abstract

MicroRNA-93 (miR-93) has been implicated in the pathogenesis of myelodysplastic syndrome (MDS), though its precise role in the regulation of hematopoiesis and cell fate in MDS remains poorly understood. This study aimed to investigate the impact of miR-93 on cell proliferation, apoptosis, and hematopoiesis in MDS, focusing on the PAG1-mediated EGFR signaling pathway. Bioinformatic analyses were used to identify the miR-93-PAG1-EGFR axis in MDS. Gain- and loss-of-function experiments were performed using miR-93 mimics, miR-93 inhibitors, and siRNA targeting PAG1 to evaluate their roles in MDS progression. Bone marrow mononuclear cells from MDS patients were analyzed to assess the molecular expression patterns. Our findings revealed elevated miR-93 expression and reduced PAG1 levels, alongside activation of the EGFR signaling pathway in MDS patient samples. Downregulation of miR-93 or activation of PAG1 reversed these molecular alterations. Specifically, reduced miR-93 levels led to decreased EGFR phosphorylation and upregulation of PAG1 expression, which resulted in suppressed MDS cell proliferation, increased apoptosis, and enhanced hematopoiesis. Furthermore, the expression of key signaling molecules, including c-fos, TNF-α, IL-3, and stem cell factor (SCF), was modulated in response to miR-93 or PAG1 regulation. This study demonstrates that downregulation of miR-93 suppresses MDS progression through the inactivation of the EGFR signaling pathway and the upregulation of PAG1. Our results suggest that targeting the miR-93/PAG1/EGFR axis could offer potential therapeutic strategies for managing myelodysplastic syndrome (MDS) and promoting hematopoiesis.