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Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol‐Associated Hepatitis
Author(s) -
Yang Zhihong,
Zhang Ting,
Kusumanchi Praveen,
Tang Qing,
Sun Zhaoli,
Radaeva Svetlana,
Peiffer Brandon,
Shah Vijay H.,
Kamath Patrick,
Gores Greg J.,
Sanyal Arun,
Chalasani Naga,
Jiang Yanchao,
Huda Nazmul,
Ma Jing,
Liangpunsakul Suthat
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31994
Subject(s) - microrna , cancer research , biology , oncogene , transcriptome , cell cycle , gene expression profiling , cyclin d2 , cyclin d1 , medicine , oncology , gene , gene expression , genetics
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.