Schizophrenia-associated microRNA-148b-3p regulates COMT and PRSS16 expression by targeting the ZNF804A gene in human neuroblastoma cells

Abstract

Zinc finger protein 804A ( ZNF804A) has been identified by genome-wide association studies as a robust risk gene in schizophrenia, but how ZNF804A contributes to schizophrenia and its upstream regulation remains unknown. Previous studies have indicated that microRNAs (miRs) are key factors that regulate the expression levels of their target genes. The present study revealed significantly increased expression of miR-148b-3p in the peripheral blood of patients with first-onset schizophrenia compared with healthy controls, and bioinformatics analysis predicted that the ZNF804A gene is a target of miR-148b-3p. Therefore, the present study investigated the possible upstream regulation of ZNF804A by miR-148b-3p in the human neuroblastoma SH-SY5Y cell line, and assessed the implications for schizophrenia. The results revealed significantly reversed expression levels of miR-148b-3p (P=0.0051) and ZNF804A (P=0.0218) in the peripheral blood of patients with first-onset schizophrenia compared with healthy individuals. Furthermore, it was demonstrated that miR-148b-3p directly targeted ZNF804A via binding to conserved target sites in the 3′-untranslated region of ZNF804A mRNA, where it inhibited the endogenous expression of ZNF804A at both the mRNA (P=0.048) and protein levels (P=0.013) in SH-SY5Y cells. Furthermore, miR-148b-3p was revealed to regulate the expression levels of catechol- O-methyltransferase ( COMT) and serine protease 16 ( PRSS16) by targeting ZNF804A in SH-SY5Y cells. Collectively, the present results indicated that there was a direct upstream regulation of the schizophrenia risk gene ZNF804A by miR-148b-3p, which contributed to the regulation of the downstream genes COMT and PRSS16. Thus, the miR-148b-3p/ ZNF804A/COMT/PRSS16 pathway may play an important role in the pathophysiology of schizophrenia, and may serve as a potential target in drug discovery and gene therapy for this disorder.