Mechanistic roles of microRNAs in hepatocarcinogenesis: A study of thioacetamide with multiple doses and time-points of rats

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.

Detection of increased serum miR-122-5p and miR-455-3p levels before the clinical diagnosis of liver cancer in people with type 2 diabetes

“…Overexpression of miR-455-3p inhibited tumour growth in prostate cancer 31 and renal carcinoma cells 32 . In a rat model of thioacetamide-induced hepatocellular carcinoma, decreased expression of miR-455-3p was detected during early stage of cancer development 33 . The same study also identified miR-34a-5p as an early marker for hepatocellular carcinoma although we did not detect any difference in miR-34a-5p between patients with or without LC (Supplementary Table S8 ).…”

Acute Bone Damage Through Liver-bone Axis Induced by Thioacetamide in Rats

“…Some scholars have also found that TAA not only damages the liver of animals, but also affects the kidneys, brain, spleen, and bone of animals(Al-Bader et al 2000; Kleinfeld 1957;Lassila and Virtanen 1984b;Saran et al 2004). When the liver of animal model was treated by TAA, the enzyme metabolism of the liver, protein, adipose, amino acid and the messenger RNA were changed to varying degrees compared with the normal group (Dweep et al 2017;Fontana et al 1996;Nozu et al 1992;Okuyama et al 2005;Waters et al 2005). However, most scholars are concerned about the role of TAA in the liver and its mechanism.…”

“…In recent years, some researchers pay attention to the reason of TAA caused liver damage, TAA mediated by microsomal CYP2E1 to TAA-S or S-dioxide that initiates cellular necrosis (Chilakapati et al 2005), Karantonis suggested that reducing the levels of reactive oxygen species may improve liver damage (Pallottini et al 2006), the platelet-activating factor had implicating participation in liver brotic process (Karantonis et al 2010). Then, other researchers explored how to inhibit TAA toxicity in liver, hepatic irradiation preconditioning enhances the effect of bone marrow-derived mesenchymal stem cell improving TAA-induced liver brosis in rats (Shao et al 2014), a study demonstrate that a small-molecule inhibitor of connexin 32 can protect against liver failure and death in wild-type mice when co-administered with TAA (Patel et al 2012), as well as miR-34a-5p that is microRNA was the most suitable early and sensitive biomarker for TAA-treated hepatic carcinoma (Dweep et al 2017). In addition, metabolic bone disease is common among patients with chronic liver disease (Compston 1986; Rouillard and Lane 2001), chronic liver disease is associated with alterations in receptor activator of nuclear factor kB ligand and osteoprotegerin serum levels, which could affect bone metabolism (Moschen et al 2005).…”

Evaluation of Bioinformatics Approaches for Next-Generation Sequencing Analysis of microRNAs with a Toxicogenomics Study Design

“…The data used in this analysis is reported from our lab ( Dweep et al, 2017 ) and available in the GEO repository (GSE87446) 1 . Briefly, thioacetamide was administered to rats for 3, 7, 14, and 28 days with 4.5, 15, and 45 g/kg, daily.…”