Abstract
Environmental chemicals exposure is one of the primary factors for liver toxicity and hepatocarcinoma. Thioacetamide (TAA) is a well-known hepatotoxicant and could be a liver carcinogen in humans. The discovery of early and sensitive microRNA (miRNA) biomarkers in liver injury and tumor progression could improve cancer diagnosis, prognosis, and management. To study this, we performed next generation sequencing of the livers of Sprague-Dawley rats treated with TAA at three doses (4.5, 15 and 45 mg/kg) and four time points (3-, 7-, 14- and 28-days). Overall, 330 unique differentially expressed miRNAs (DEMs) were identified in the entire TAA-treatment course. Of these, 129 DEMs were found significantly enriched for the “liver cancer” annotation. These results were further complemented by pathway analysis (Molecular Mechanisms of Cancer, p53-, TGF-β-, MAPK- and Wnt-signaling). Two miRNAs (rno-miR-34a-5p and rno-miR-455-3p) out of 48 overlapping DEMs were identified to be early and sensitive biomarkers for TAA-induced hepatocarcinogenicity. We have shown significant regulatory associations between DEMs and TAA-induced liver carcinogenesis at an earlier stage than histopathological features. Most importantly, miR-34a-5p is the most suitable early and sensitive biomarker for TAA-induced hepatocarcinogenesis due to its consistent elevation during the entire treatment course.
Highlights
Environmental chemicals exposure is one of the primary factors for liver toxicity and hepatocarcinoma
Treatment Distribution of 330 differentially expressed miRNAs (DEMs) Low dose Middle dose High dose Total DEMs Common DEMs Dose- and time-dependent DEMs Dose-dependent DEMs Time-dependent DEMs Diseases or functional association and sensitive biomarkers based on these 330 DEMs and to decipher their roles in liver cancer and related biological signaling pathways
A disease/function enrichment analysis was conducted using Ingenuity Pathway Analysis (IPA) to identify the pathophysiological association of DEMs during three different doses and four time intervals (12 treatment conditions), which resulted in 22 diseases or functions significantly enriched (Table S2)
Summary
Environmental chemicals exposure is one of the primary factors for liver toxicity and hepatocarcinoma. We designed a toxicogenomics experiment involving multiple doses and treatment durations to study microRNA (miRNA) expression of TAA-induced carcinogenicity, further our knowledge to NGTCs. Toxicogenomics has been extensively used for the study of environmental carcinogens[17]. We examined the change in the expression profile of miRNAs over multiple doses and time-points of treatment with TAA using NGS technology (miRNA sequencing or miRNA-seq). A new integrative bioinformatics workflow was applied to identify differentially expressed miRNAs (DEMs) and their possible regulatory roles within the signaling cascades which could be involved in TAA-induced hepatocarcinogenicity (Fig. 1). MiR-122, which is a commonly studied circulating miRNA biomarker for liver injury, was not differentially expressed according to neither dose nor time point in the liver tissues treated with TAA
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