Suppression of MicroRNA-219-5p Activates Keratinocyte Growth Factor to Mitigate Severity of Experimental Cirrhosis

Abstract

Background/Aims: Keratinocyte growth factor (KGF) plays a critical role in prevention of cirrhosis and enhancement of liver regeneration. However, the molecular regulation of KGF in liver is unknown. MicroRNAs (miRNAs) control the pathogenesis of cirrhosis, whereas the exact involved miRNAs and molecular signaling pathways remain ill-defined. Here we addressed these questions. Methods: We examined the correlation of the levels of miR-219-5p and KGF in the liver biopsies from patients with liver diseases. The effects of overexpression or suppression of miR-219-5p on KGF were examined in both human and mouse hepatic stellate cells (HSCs). Bioinformatics analysis was applied to examine the binding of human/mouse miR-219-5p to the 3'-UTR of human/mouse KGF mRNA, respectively. Finally, adeno-associated viruses carrying antisense of miR-219-5p were infused into the liver from the mice that had developed cirrhosis by carbon tetrachloride (CCl4), and the effects on KGF levels and liver damage and function were examined. Results: The levels of miR-219-5p and KGF in the liver biopsies were inversely correlated. MiR-219-5p inhibited KGF expression in both human and mouse HSCs, through directly binding the 3'-UTR of KGF mRNA. Expression of antisense of miR-219-5p significantly attenuated the levels of liver fibrosis, portal hypertension and sodium retention caused by CCl4. Conclusions: Suppression of miR-219-5p may benefit the liver regeneration and prevent cirrhosis through increasing KGF.

Keywords

• Cirrhosis
• MiR-219-5p
• Carbon tetrachloride (CCl4)
• Keratinocyte growth factor (KGF)