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

Abstract

This study was designed to investigate the potential role of microRNA-29c (miR-29c) in biliary atresia-related fibrosis. The expression of miR-29c was determined in 15 pairs of peripheral blood samples from infants with biliary atresia (BA) and infants with non-BA neonatal cholestasis using quantitative real-time PCR. EMT was established by induction with TGF-β1 in HIBEpiC cells. MiR-29c was inhibited by lipofectamine transfection. The expressions of proteins related to epithelial–mesenchymal transition (EMT), i.e., E-cadherin, N-cadherin and vimentin, were determined using quantitative real-time PCR and western blotting. Direct interaction between miR-29c and DNMT3A and DNMT3B was identified using a luciferase reporter assay. The expressions of DNMT3A and DNMT3B were suppressed by treatment with SGI-1027. Patients with BA showed significantly lower miR-29c levels in peripheral blood samples than the control subjects. In vitro, TGF-β1-induced EMT significantly decreased the expression of miR-29c. Downregulation of miR-29c had a promotional effect on BA-related fibrosis in HIBEpiC cells, as confirmed by the decrease in E-cadherin and increase in N-cadherin and vimentin levels. MiR-29c was found to target the 3’UTR of DNMT3A and DNMT3B and inhibit their expression. Suppression of DNMT3A and DNMT3B reversed the effects of miR-29c downregulation on BA-related fibrosis in HIBEpiC cells. These data suggest that BA-related fibrosis is closely associated with the occurrence of EMT in HIBEpiC cells. MiR-29c might be a candidate for alleviating BA-related fibrosis by targeting DNMT3A and DNMT3B.

Long non‐coding RNA SOX21‐AS1 enhances the stemness of breast cancer cells via the Hippo pathway

“…The Hippo signaling pathway inhibits cell growth [29]. In mammals, upstream membrane protein receptors of the Hippo signaling pathway receive extracellular growth-inhibitory signals [30]. Once the extracellular growth-inhibitory signals are sensed, they activate a series of kinase cascade phosphorylation reactions and eventually phosphorylate downstream effector YAP and TAZ [31].…”

Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia – a pilot study

“…Wang et al . [ 43 ], Szabo and Bala [ 44 ] and Kriegel et al . [ 45 ] showed that low levels of mir-29 are associated with an increase in fibrosis in BA patients.…”

“…High levels of mir-29 have been shown to have anti-fibrotic effects by suppressing collagen 1 A1 mRNA and its protein expression, reducing HSC activation [42]. Wang et al [43], Szabo and Bala [44] and Kriegel et al [45] showed that low levels of mir-29 are associated with an increase in fibrosis in BA patients. Our results showed that miR-29b-3p was expressed at low levels in all samples, except sample 6 (BASM), where no expression was found.…”

The Role of GLI in the Regulation of Hepatic Epithelial–Mesenchymal Transition in Biliary Atresia

“…The inflammatory fibrosis process in bile ducts is regulated by several pathways, such as the Notch and transforming growth factor-β/Smad signaling pathways ( 7 ). Recent studies have shown that the Sonic hedgehog (Shh) signaling pathway and epithelial–mesenchymal transition (EMT) may also play an important role in this process ( 8 , 9 ). The Shh signaling pathway is involved in embryonic development, and several studies have suggested that the GLI family, the crucial factors of the Shh pathway, is highly expressed in the BA process ( 10 , 11 ).…”