MiR-490-3p Inhibits Cell Proliferation By Regulation Of HnRNPA1/2/3

Alternative splicing is an important event for cell proliferation and differentiation and involved in many diseases, and it occurs in more than95percent of human genes. HnRNPAs play key roles in alternative splicing. Alternative splicing of PKM, the metabolic pathway regulator, is controlled by both hnRNPA1/A2and PTB, which influences cell proliferation, differentiation and oncogenesis. New regulation factors of hnRNPAs will provide new insight into mechanism of cell differentiation, which contribute to development of diagnosis/therapy targets for related diseases. In this study, evolution and post-transcriptional regulation of hnRNPAs were analyzed and the main results are as follows.1. Close synteny even sharing of promoter region was observed in hnRNPAl/A2and CBX5/3genes in vertebrates. In human, hnRNPAl/A2and CBX5/3genes were regulated by a single bidirectional promoter. These results indicated the importance of co-regulation of hnRNPAl/CBX5or hnRNPA2/CBX3in gene regulation.2. Several miRNA targets within3’-UTR regions of hnRNPA1/A2/A3were detected by TargetScan, which are conserved in mammals. Each hnRNPA1/A2/A3contains one or more target site(s) of miR-490-3p. Duel-luciferase assays showed that miR-490-3p down-regulated hnRNPAl/A2/A3. Both target sites of hnRNPAl are active, and mutations of both sites affected its function. Over-expression of miR-490-3p significantly down-regulated mRNA levels and protein levels of hnRNPAl/A2/A3in HEK293T and H9C2, consequentially, PKM1was up-regulated. However, this inhibition of hnRNPAl can be recovered by over-expressing hnRNPA1. These results suggested that cell proliferation is controlled by miR-490-3p through alternative splicing of metabolic regulator PKM1, a regulatory process of miR-490-3p-hnRNPA1/A2/A3-PKM1.3. Mouse model of heart injury ndicated that miR-490-3p was released into plasma after heart injury, and also down-regulated in heart tissue. The down-regulation of miR-490-3p resulted in a significant up-regulation of hnRNPA1, suggesting an important role of miR-490-3p in protein synthesis and recovery of heart function when injury. In addition, miR-490-3p may be a new potential marker in diagnosis of heart injury.