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抑制 microRNA-29c 通过靶向 DNMT3A 和 DNMT3B 促进先天性胆道闭锁相关纤维化。

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

机构信息

1Department of General Surgery, Shenzhen Children's Hospital, Shenzhen, 518026 Guangdong Province China.

2Graduate School of China Medical University, Shenzhen, 110122 Liaoning Province China.

出版信息

Cell Mol Biol Lett. 2019 Mar 11;24:10. doi: 10.1186/s11658-018-0134-9. eCollection 2019.

DOI:10.1186/s11658-018-0134-9
PMID:30906331
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6410490/
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.

摘要

本研究旨在探讨 microRNA-29c（miR-29c）在胆道闭锁相关纤维化中的潜在作用。采用实时定量 PCR 法检测 15 对胆道闭锁（BA）患儿和非 BA 新生儿胆汁淤积患儿外周血样本中 miR-29c 的表达。用 TGF-β1 诱导 HIBEpiC 细胞建立 EMT 模型。用脂质体转染抑制 miR-29c 的表达。采用实时定量 PCR 和 Western blot 法检测上皮-间充质转化（EMT）相关蛋白 E-钙黏蛋白、N-钙黏蛋白和波形蛋白的表达。采用荧光素酶报告基因实验鉴定 miR-29c 与 DNMT3A 和 DNMT3B 之间的直接相互作用。用 SGI-1027 处理抑制 DNMT3A 和 DNMT3B 的表达。BA 患儿外周血样本中 miR-29c 水平明显低于对照组。体外，TGF-β1 诱导的 EMT 显著降低 miR-29c 的表达。下调 miR-29c 可促进 HIBEpiC 细胞中与 BA 相关的纤维化，E-钙黏蛋白水平降低，N-钙黏蛋白和波形蛋白水平升高证实了这一点。miR-29c 被发现靶向 DNMT3A 和 DNMT3B 的 3'UTR 并抑制其表达。抑制 DNMT3A 和 DNMT3B 逆转了 miR-29c 下调对 HIBEpiC 细胞中 BA 相关纤维化的影响。这些数据表明，BA 相关纤维化与 HIBEpiC 细胞中 EMT 的发生密切相关。miR-29c 可能通过靶向 DNMT3A 和 DNMT3B 成为缓解 BA 相关纤维化的候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/4cab4dd4a209/11658_2018_134_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/af11ed91de38/11658_2018_134_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/6a05ba60f8b4/11658_2018_134_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/4b956afe1ce4/11658_2018_134_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/1e6f917ffa1d/11658_2018_134_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/4cab4dd4a209/11658_2018_134_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/af11ed91de38/11658_2018_134_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/6a05ba60f8b4/11658_2018_134_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/4b956afe1ce4/11658_2018_134_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/1e6f917ffa1d/11658_2018_134_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d5c/6410490/4cab4dd4a209/11658_2018_134_Fig5_HTML.jpg

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