Identification of miR-194 potential target genes and signaling pathways in the liver fibrosis
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Taha Aghajanzadeh,1 Mahmood Talkhabi,2 Mohammad Reza Zali,3 Behzad Hatami,4 Kaveh Baghaei,5,*
1. Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
2. Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University
3. Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences
4. Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences
5. Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences
- Introduction: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease, ranging from steatosis to non-alcoholic steatohepatitis (NASH) with increased risk of fibrosis, cirrhosis, and cancer. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, mainly collagen fibers. Activation of hepatic stellate cells (HSCs) from the quiescent state is responsible for the exceeding collagen production. Previous studies have reported the down-regulation of miR-194 in activated HSCs (aHSCs), but more shreds of evidence are needed for better understanding of the exact cellular and molecular mechanisms. Here, we aim to investigate the potential role of miR-194 down-regulation in liver fibrosis through its target genes.
- Methods: We extracted the miRNA-target genes interactions (MTIs) of hsa-miR-194-5p from various databases, including miRTarBase and TarBase 8 for experimentally validated and Target scan, miRWalk, miRDB, and DIANA-microT for predicted MTIs. For more accurate results, we selected only the genes associated with NAFLD using the DisGeNET database (UMLS IDs “C0015695”, “C0400966”, and “C3241937”). We constructed protein-protein interaction (PPI) network using STRING and visualized it by Cytoscape software. Finally, we used the enrichR online tool to perform pathway and functional enrichment analyses.
- Results: Our study identified a total of 27 and 207 genes in common for validated and predicted MTIs, respectively. After comparing to the DisGeNET database, 24 genes overlapped between target genes and NAFLD-associated ones. The PPI network identified 11 genes, including SMURF1, CAV1, TMED2, FBXW7, ACVR2B, YAP1, FOXA1, GOT2, IL10, IL6ST, and SYVN1, have interactions together, while the others were disconnected from the network. Also, SMURF1 had the most connections, with a degree score of 3. These genes are supposed to be up-regulated due to the down-regulation of miR-194. Pathway analysis revealed significant enrichment in the BMP, ALK1, Ubiquitin-mediated proteolysis, TGF-beta, Delta Np63, p53, and NOTCH signaling pathways in addition to Cytokine-cytokine receptor interactions in the activation of HSCs. We expanded the PPI network by adding ten more interactors, and the new pathway analysis showed that SKP1, BMP2, SMAD7, and SEL1L are also involved in the previous signaling pathways.
- Conclusion: Collectively, our findings identified the miR-194 potential related genes and signaling pathways, which can be implemented to uncover the underlying mechanisms responsible for the activation of HSCs and progression of liver fibrosis.
- Keywords: hepatic stellate cells, miR-194, MTI, PPI, signaling pathway
