BioProject

Environmental chemicals exposure are one of the primary factors for liver toxicity and hepatocarcinoma. More...

Environmental chemicals exposure are 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 biomarkers in liver injury and tumor progression could improve cancer diagnosis, prognosis, and management. In the present study, we studied the dynamic changes in microRNAs (miRNAs) expression and explored the potential mechanistic role of miRNAs in rat liver treated with TAA at multiple doses and time points. Sprague-Dawley rats were administrated with TAA at three doses [low (4.5 mg/kg), middle (15mg/kg) and high (45mg/kg)] and four repeated treatment durations (3-, 7-, 14- and 28-days). Expressions of miRNAs in livers were profiled using next generation sequencing and analyzed. 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 in which “Molecular Mechanisms of Cancer”, “p53-”, “TGF-β-”, “MAPK-” and “Wnt-signaling” were significantly enriched in most TAA-treatment conditions. Two miRNAs (rno-miR-34a-5p and rno-miR-455-3p) out of 48 DEMs (common across all the treatment conditions) were identified to be early and sensitive biomarkers for TAA-induced hepatocarcinogenicity. Upregulation of rno-miR-34a-5p was further confirmed by qPCR. These findings reveal the critical role of miRNAs in the mechanisms underlying hepatocarcinogenesis and potential application for human risk assessment. Most importantly, rno-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. Overall design: The animal study was conducted as described previously (Uehara 2011). Briefly, male Sprague-Dawley (SD) rats were consecutively administered with TAA once daily at doses of 4.5 (low dose), 15 (middle dose), or 45 (high dose) mg/kg for 3, 7, 14, and 28 days (referred as 3-d, 7-d, 14-d and 28-d hereafter) with the time-matched control group receiving vehicle alone. Less...