Identification of Urinary microRNA Profiles in Rats That May Diagnose Hepatotoxicity

Yang, Xi; Greenhaw, James; Shi, Qiang; Su, Zhenqiang; Qian, Feng; Davis, Kelly J.; Mendrick, Donna L.; Salminen, William F.

doi:10.1093/toxsci/kfr321

Cited by 75 publications

(48 citation statements)

References 41 publications

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“…While urine is beginning to be more widely used (Yang et al, 2012; Kanki et al, 2014; Yang et al, 2015), field-collected samples are still rarely measured. In this study, we were able to successfully isolate and quantify miRNA expression in field collected urine samples that had be archived in our biorepository.…”

Section: Discussionmentioning

confidence: 99%

Urinary microRNAs as potential biomarkers of pesticide exposure

Weldon

Shubin

Smith

et al. 2016

Toxicology and Applied Pharmacology

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MicroRNAs (miRNAs) are post-transcriptional regulators that silence messenger RNAs. Because miRNAs are stable at room temperature and long-lived, they have been proposed as molecular biomarkers to monitor disease and exposure status. While urinary miRNAs have been used clinically as potential diagnostic markers for kidney and bladder cancers and other diseases, their utility in non-clinical settings has yet to be fully developed. Our goal was to investigate the potential of urinary miRNAs to act as biomarkers of pesticide exposure and early biological response by identifying the miRNAs present in urine from 27 parent/child, farmworker/non-farmworker pairs (16FW/11NFW) collected during two agricultural seasons (thinning and post-harvest) and characterizing the between- and within-individual variability of these miRNA epigenetic regulators. MiRNAs were isolated from archived urine samples and identified using PCR arrays. Comparisons were made between age, households, season, and occupation. Of 384 miRNAs investigated, 297 (77%) were detectable in at least one sample. Seven miRNAs were detected in at least 50% of the samples, and one miRNA was present in 96% of the samples. Principal components and hierarchical clustering analyses indicate significant differences in miRNA profiles between farmworker and non-farmworker adults as well as between seasons. Six miRNAs were observed to be positively associated with farmworkers status during the post-harvest season. Expression of five of these miRNA trended towards a positive dose response relationship with organophosphate pesticide metabolites in farmworkers. These results suggest that miRNAs may be novel biomarkers of pesticide exposure and early biological response.

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Section: Discussionmentioning

confidence: 99%

Urinary microRNAs as potential biomarkers of pesticide exposure

Weldon

Shubin

Smith

et al. 2016

Toxicology and Applied Pharmacology

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“…The miRNeasy Serum/Plasma Kit (Qiagen) was used to purify total miRNAs in cell medium, with the C. elegans miR-39 (cel-miR-39) as the Spike-in control, according to the manufacturer’s protocol. Total RNA in serum was extracted using TRIzol (Invitrogen, Carlsbad, CA) methods as described previously (Yang et al 2012). …”

Section: Methodsmentioning

confidence: 99%

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

Gill

et al. 2017

Arch Toxicol

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Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) Hep-aRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6–559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

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“…3A). Interestingly, miR-21 and miR-29b are reported circulatory miRNAs able to integrate into surrounding cells acting as paracrine signaling molecules (14,(18)(19)(20)(21)(22). In addition, it was recently discovered that miR-21 is able to bind to TLR8 located within endosomes of immune cells to induce an inflammatory response (16).…”

Section: Mirnas Are Involved In Il6-mediated Cancer Immune Cell Crossmentioning

confidence: 99%

IL6 Mediates Immune and Colorectal Cancer Cell Cross-talk via miR-21 and miR-29b

Patel

Gooderham

2015

Molecular Cancer Research

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Tumors are surrounded and infiltrated by a variety of stromal cell types, including fibroblasts, immune cells, and vascular endothelial cells, which interact with malignant cells to generate the tumor microenvironment (TME). This complex environment is thought to be regulated by the tumor in order to promote its survival and progression and thus constitutes a potential target for cancer therapy. However, intercellular communication within the microenvironment is not yet well understood. The current study investigates the mechanism by which cancer and immune cells communicate using an in vitro coculture model. It is demonstrated that IL6, a proinflammatory cytokine, secreted by immune cells promotes colorectal cancer cell invasiveness. In addition, in the presence of IL6, the cancer cells were able to secrete circulating miRNAs miR-21 and miR-29b to further induce immune cell IL6 production. Activated immune cells were also found to release miR-21 into the TME. Taken together, these mechanistic findings provide a better understanding of intercellular communication between immune and cancer cells in the TME and offer insight into some of the key players that mediate this cross-talk.Implications: This study demonstrates that cocultured cancer and immune cells communicate via IL6 and circulating miRNAs to sustain chronic inflammation and promote prometastatic cancer cell behavior. In addition, critical players are identified that mediate intercellular communication in the TME and suggest possible therapeutic approaches that target the microenvironment.

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Identification of Urinary microRNA Profiles in Rats That May Diagnose Hepatotoxicity

Cited by 75 publications

References 41 publications

Urinary microRNAs as potential biomarkers of pesticide exposure

Urinary microRNAs as potential biomarkers of pesticide exposure

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

IL6 Mediates Immune and Colorectal Cancer Cell Cross-talk via miR-21 and miR-29b

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