Abstract
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”.
Highlights
MicroRNAs are regarded as a promising source of tissue-specific biomarkers
The amount of circulating miRNAs isolated from serum of subject with impairments was significantly higher (p-value = 0.003218) than the miRNA yield isolated from serum samples of healthy subjects
Apart from miR-22-3p which increased from 7% in the healthy subjects (HC) to 21% in the APAP samples, the composition of the most abundant miRNAs in APAP, HBV, liver cirrhosis (LC) and type 2 diabetes mellitus (T2DM) was comparable to HC (S3 Table)
Summary
MicroRNAs (miRNAs) are regarded as a promising source of tissue-specific biomarkers. These small noncoding RNAs of about 22 nucleotides regulate post-transcriptional gene expression by base pairing with the 3’ untranslated region of the target genes resulting in repressed protein production from the respective gene. MicroRNAs are known to regulate most protein-coding transcripts and are involved in many biological processes [1]. Many miRNA species have been identified as tissue-specific [2]. As a result of tissue damage, and/or active secretion, miRNAs are released into the blood circulation [3]. MiRNAs are stable as they are incorporated within microvesicles or bind to proteins that protect them from RNase digestion [4]
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