Serum microRNA signatures as "liquid biopsies" for interrogating hepatotoxic mechanisms and liver pathogenesis in human

• Published in: PloS one Vol. 12; no. 5; p. e0177928
• Main Authors: Krauskopf, Julian, de Kok, Theo M, Schomaker, Shelli J, Gosink, Mark, Burt, Deborah A, Chandler, Patricia, Warner, Roscoe L, Johnson, Kent J, Caiment, Florian, Kleinjans, Jos C, Aubrecht, Jiri
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.05.2017; Public Library of Science (PLoS)
• Subjects: 3-Aminobutyric acid; Acetaminophen; Adenylation; Adhesion; Adult; Age; Alanine; Alcohols; Alkaline phosphatase; Analgesics; Analysis; Antigen presentation; Arches; Aspartate aminotransferase; Beta cells; Bilirubin; Biological activity; Biology and life sciences; Biomarkers; Biomarkers - blood; Biopsy; Blood; Blood circulation; Brain; Brain injury; Cell death; Chemical and Drug Induced Liver Injury - genetics; Chemotaxis; Developmental stages; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Disease; Drug overdose; Family medical history; Female; Females; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation; Gene Regulatory Networks; Genetic Predisposition to Disease; Glucose; Health care; Heart; Heart diseases; Hepatitis; Hepatitis B - genetics; Hepatotoxicity; High-Throughput Nucleotide Sequencing - methods; Humans; Infections; Infectious diseases; Inhibition; Injuries; Insulin; Interferon; Kinases; Liver; Liver cirrhosis; Liver Cirrhosis - genetics; Male; Males; Medicine and Health Sciences; Metabolic disorders; Metabolism; Mice; MicroRNA; MicroRNAs; MicroRNAs - blood; Multiplexing; Nitrogen; Nucleotide sequence; Nucleotides; Overdose; Oxidative stress; Pathogenesis; Pathology; Physical Sciences; Pneumonia; Product safety; Proteins; R&D; Research & development; Research and analysis methods; Ribonucleic acid; RNA; Safety; Safety research; Signatures; Toxicity; Viruses; Ann Arbor Michigan; United States > US; Connecticut; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0177928

MicroRNAs (miRNAs) released into the peripheral circulation upon cellular injury have shown a promise as a new class of tissue-specific biomarkers. We were first to demonstrate that next-generation sequencing analysis of serum from human subjects with acetaminophen-induced liver injury revealed a specific signature of circulating miRNAs. We consequently hypothesized that different types of hepatic liver impairments might feature distinct signatures of circulating miRNAs and that this approach might be useful as minimally invasive diagnostic "liquid biopsies" enabling the interrogation of underlying molecular mechanisms of injury in distant tissues. Therefore we examined serum circulating miRNAs in a total of 72 serum samples from a group of 53 subjects that included patients with accidental acetaminophen overdose, hepatitis B infection, liver cirrhosis and type 2 diabetes as well as gender- and age-matched healthy subjects with no evidence of liver disease. The miRNA signatures were identified using next-generation sequencing that provided analysis for the whole miRNome, including miRNA isoforms. Compared to the healthy subjects, a total of 179 miRNAs showed altered serum levels across the diseased subjects. Although many subjects have elevated alanine aminotransferase suggesting liver impairments, we identified distinct miRNA signatures for different impairments with minimum overlap. Furthermore, the bioinformatics analysis of miRNA signatures revealed relevant molecular pathways associated with the mechanisms of toxicity and or pathogenesis of disease. Interestingly, the high proportion of miRNA isoforms present in the respective signatures indicated a new level of complexity in cellular response to stress or disease. Our study demonstrates for the first time that signatures of circulating miRNAs show specificity for liver injury phenotypes and, once validated, might become useful for diagnosis of organ pathologies as "liquid biopsies".