Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol-Associated Hepatitis
| Autor: | Suthat Liangpunsakul, Yanchao Jiang, Ting Zhang, Jing Ma, Patrick S. Kamath, Arun J. Sanyal, Svetlana Radaeva, Zhaoli Sun, Nazmul Huda, Brandon J. Peiffer, Qing Tang, Naga Chalasani, G. J. Gores, Zhihong Yang, Praveen Kusumanchi, Vijay H. Shah |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male medicine.medical_treatment Liver transplantation Severity of Illness Index Article Body Mass Index Transcriptome End Stage Liver Disease Liver disease Cyclin D1 Cyclin D2 medicine Humans 3' Untranslated Regions Hepatitis Hepatology business.industry Hepatitis Alcoholic Gene Expression Profiling Cell cycle Middle Aged medicine.disease Liver regeneration Liver Regeneration Liver Transplantation Up-Regulation MicroRNAs Liver Case-Control Studies Cancer research Hepatocytes Female business Biomarkers Follow-Up Studies |
| Zdroj: | Hepatology |
| ISSN: | 1527-3350 |
| Popis: | Background and aims We conducted a comprehensive serum transcriptomic analysis to explore the roles of microRNAs (miRNAs) in alcohol-associated hepatitis (AH) pathogenesis and their prognostic significance. Approach and results Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, expression of miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell-cycle progression pathways, including ribonucleotide reductase regulatory subunit M2 (RRM2), cyclin D1 (CCND1), cyclin D2 (CCND2), MYC proto-oncogene (MYC), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1). We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1, in AH patients who underwent liver transplantation; miR-26b-5p and miR-30b-5p inhibited the 3'-UTR (untranslated region) luciferase activity of RRM2 and CCND2, and miR-20a-5p reduced the 3'-UTR luciferase activity of CCND1 and CCND2. During a median follow-up of 346 days, 21% of AH patients died; these patients had higher body mass index (BMI), Model for End-Stage Liver Disease (MELD), and serum miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p than those who survived. Cox regression analysis showed that BMI, MELD score, miR-20a-5p, miR-146a-5p, and miR-26b-5p predicted mortality. Conclusions Patients with AH attempt to deal with hepatocyte injury by down-regulating specific miRNAs and up-regulating genes responsible for DNA synthesis and cell-cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short-term mortality in AH patients. |
| Databáze: | OpenAIRE |
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