Integrated analysis of hepatic miRNA and mRNA expression profiles in the spontaneous recovery of liver fibrosis [mRNA]

Liver fibrosis, results from the imbalance between extracellular matrix (ECM) production and degradation, is a common pathological consequence of various chronic liver diseases. Although a large number of miRNAs have been reported in liver fibrosis progression, miRNA-mRNA interactions involved in its reversal process remain to be fully elucidated. In the current study, we performed an integrated analysis of miRNA and mRNA expression profiles in a hepatic fibrosis recovery mouse model induced by thioacetamide. A total of 102 miRNA and 2,845 mRNAs showed significant differential expression in recovery mice compared to fibrotic mice. Moreover, 3,769 putative negatively correlated miRNA-mRNA pairs were revealed to be potentially implicated in the biological function regulation of small molecule metabolism and ECM organization. By integrating miRNA-mRNA regulatory networks, mmu-miR-1843a-5p, mmu-miR-193a-5p, mmu-miR-194-2-3p and mmu-miR-30c-2-3p were identified as lysyl oxidase-specific miRNAs that were associated with the pathogenesis of fibrosis recovery. Our results provide potential novel biomarkers and candidate targets for the treatment of liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of thioacetamide (TAA) for 8 weeks. Control mice received the same volume of normal saline (NS). Liver fibrosis recovery model (Recovery) was established via 8-week TAA injection and then withdrew the repeated liver damages, following by spontaneous recovery for additional 8 weeks. mRNA expression profile was performed in the liver tissues of TAA-fibrotic mice, recovery mice and control mice.

肝纤维化（liver fibrosis）是由细胞外基质（extracellular matrix, ECM）合成与降解失衡所导致的常见病理结局，可继发于多种慢性肝脏疾病。尽管已有大量微小RNA（microRNA, miRNA）被报道与肝纤维化进展相关，但参与其逆转过程的miRNA-mRNA互作机制仍有待全面阐明。在本研究中，我们对硫代乙酰胺（thioacetamide, TAA）诱导的肝纤维化恢复小鼠模型的miRNA与mRNA表达谱开展了整合分析。相较于纤维化模型小鼠，恢复组小鼠中共鉴定出102个差异表达miRNA以及2845个差异表达mRNA。此外，研究共发现3769对潜在负调控的miRNA-mRNA关联对，这些关联对可能参与小分子代谢与细胞外基质组织的生物学功能调控。通过整合miRNA-mRNA调控网络，我们鉴定出mmu-miR-1843a-5p、mmu-miR-193a-5p、mmu-miR-194-2-3p及mmu-miR-30c-2-3p为赖氨酰氧化酶特异性miRNA，与纤维化恢复的发病机制密切相关。本研究结果为肝纤维化的治疗提供了潜在的新型生物标志物与候选治疗靶点。本研究通过腹腔注射硫代乙酰胺（TAA）持续8周构建肝纤维化模型，对照组小鼠则注射等体积生理盐水（normal saline, NS）。肝纤维化恢复模型（恢复组）的构建流程为：先以TAA注射8周诱导肝纤维化，随后停止造模以终止反复肝损伤，让小鼠经历8周的自发恢复过程。我们分别采集TAA诱导的纤维化模型小鼠、恢复组小鼠及对照组小鼠的肝组织，开展mRNA表达谱检测。