Suppressing microRNA-29c promotes biliary atresia-related fibrosis by targeting DNMT3A and DNMT3B

Area of Science:

• Hepatology and Gastroenterology
• Molecular Biology
• Developmental Biology

Background:

• Biliary atresia (BA) is a severe neonatal cholestatic liver disease characterized by progressive fibrosis.
• Epithelial-mesenchymal transition (EMT) plays a critical role in the pathogenesis of liver fibrosis.
• The role of microRNAs, specifically microRNA-29c (miR-29c), in BA-related fibrosis remains largely unexplored.

Purpose of the Study:

• To investigate the expression and function of miR-29c in biliary atresia-related fibrosis.
• To elucidate the molecular mechanisms underlying miR-29c's role in EMT and fibrosis in BA.
• To explore miR-29c as a potential therapeutic target for BA-related fibrosis.

Main Methods:

• Quantitative real-time PCR and western blotting were used to assess miR-29c, EMT markers (E-cadherin, N-cadherin, vimentin), DNMT3A, and DNMT3B expression.
• EMT was induced in human intrahepatic biliary epithelial cells (HIBEpiC) using TGF-β1.
• miR-29c inhibition and luciferase reporter assays were employed to determine direct targeting of DNMT3A and DNMT3B by miR-29c.

Main Results:

• Infants with BA exhibited significantly lower miR-29c levels in peripheral blood compared to controls.
• TGF-β1-induced EMT in HIBEpiC cells led to a significant decrease in miR-29c expression.
• Downregulation of miR-29c promoted fibrosis in HIBEpiC cells, evidenced by decreased E-cadherin and increased N-cadherin and vimentin. miR-29c directly targets and inhibits DNMT3A and DNMT3B expression.

Conclusions:

• BA-related fibrosis is associated with EMT in biliary epithelial cells.
• miR-29c downregulation contributes to BA-related fibrosis by promoting EMT through targeting DNMT3A and DNMT3B.
• miR-29c represents a potential therapeutic candidate for mitigating biliary atresia-related fibrosis.