Distinct response of the hepatic transcriptome to Aflatoxin B1 induced hepatocellular carcinogenesis and resistance in rats

Abstract

Aflatoxin is a natural potent carcinogen and a major cause of liver cancer. However, the molecular mechanisms of hepatocellular carcinogenesis remain largely unexplored. In this study, we profiled global gene expression in liver tissues of rats that developed hepatocellular carcinoma (HCC) from aflatoxin B1 (AFB1) administration and those that were AFB1-resistant, as well as rats without AFB1 exposure as a control. AFB1 exposure resulted in extensive perturbation in gene expression with different functions in HCC and AFB1 resistance (AR) samples. The differentially expressed genes (DEGs) in HCC sample were enriched for cell proliferation, cell adhesion and vasculature development that largely contribute to carcinogenesis. Anti-apoptosis genes were up-regulated in HCC sample whereas apoptosis-induction genes were up-regulated in AR sample. AFB1 exposure also caused extensive alteration in expression level of lncRNAs. Among all the 4511 annotated lncRNAs, half of them were highly expressed only in HCC sample and up-regulated a group of protein-coding genes with cancer-related functions: apoptosis regulation, DNA repair, and cell cycle. Intriguingly, these genes were down-regulated by lncRNAs highly expressed in AR sample. Collectively, apoptosis is the critical biological process for carcinogenesis in response to AFB1 exposure through changes in expression level of both protein-coding and lncRNA genes.

Aluminosilicate clay improves production responses and reduces inflammation during an aflatoxin challenge in lactating Holstein cows

“…Abrar et al (2013) discussed that AF toxicity results from the generation of reactive oxygen species, such as superoxide anion and hydrogen peroxide, which lead to AF metabolites adhering to DNA, RNA, intracellular membranes, and proteins. Additionally, AF exposure can lead to an increase in inflammatory-related enzymes as well as increased hepatic gene expression of proteins related to inflammatory response mechanisms, including NFKB1 and GPX1 (Bernabucci et al, 2011;Shi et al, 2016;Weatherly et al, 2018;Pate and Cardoso, 2018).…”

HAfTs are novel lncRNA transcripts from aflatoxin exposure

“…AFB1-induced changes in liver have been observed in PXR and Cyp isoforms and detoxication pathways [ 15 – 19 ]; anti-oxidant and Nrf2-related pathways [ 19 , 20 ]; cell cycle, proliferation and p53-dependent pathways [ 21 – 23 ]; as well as immune, cell adhesion and signal transduction processes [ 18 , 19 , 23 ]. RNA-Seq analysis has widened the number of cellular pathways and processes affected by AFB1 exposure in rodent, poultry and porcine models [ 24 – 31 ] including miRNAs [ 32 ] and lncRNAs [ 33 ]. The association of lncRNA changes to AFB1 exposure and development of hepatocellular carcinomas [ 33 ] is a new finding.…”

“…RNA-Seq analysis has widened the number of cellular pathways and processes affected by AFB1 exposure in rodent, poultry and porcine models [ 24 – 31 ] including miRNAs [ 32 ] and lncRNAs [ 33 ]. The association of lncRNA changes to AFB1 exposure and development of hepatocellular carcinomas [ 33 ] is a new finding. In this study [ 33 ], a 62-week exposure to AFB1 caused most rats to develop hepatocellular carcinomas while one-quarter of those similarly exposed did not, and were called–‘aflatoxin-resistant’ rats.…”

“…The association of lncRNA changes to AFB1 exposure and development of hepatocellular carcinomas [ 33 ] is a new finding. In this study [ 33 ], a 62-week exposure to AFB1 caused most rats to develop hepatocellular carcinomas while one-quarter of those similarly exposed did not, and were called–‘aflatoxin-resistant’ rats. When compared to controls, RNA-Seq revealed a large group of lncRNAs that were highly expressed only in AFB1 hepatocellular carcinomas, and was coincident with up-regulated cancer-related transcripts related to cell cycle, apoptosis, and DNA repair.…”

>b<Mutational evaluation of TP53 gene in the canine hepatocellular carcinoma>/b<: a comparative approach

“…It is also known that these mutations favor the increase of reactive oxygen species (ROS) and the reduction of antioxidant and detoxifying enzymes, such as superoxide dismutase and glutathione transferase (QIN et al, 2016). These interactions were demonstrated in experimental studies of rodents with AFB1-induced HCC, finding a suggestive feature of cellular damage by ROS, such as lipid peroxidation, besides hypermethylation, increased expression of anti-apoptotic genes (Bcl-2, MAPK8, NFKb1), and diminution of pro-apoptotic genes (Casp1, Il4, MPO) (REBBANI et al, 2015;SHI et al, 2016). In a study carried out in Brazil, the R249S mutation was demonstrated in 28% of the analyzed HCC, indicating that there is high aflatoxin exposure in the country (NOGUEIRA et al, 2009).…”